Nasal drug products and methods of their use

ABSTRACT

Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of Ser. No.14/950,707, filed on Nov. 24, 2015, which is a continuation of Ser. No.14/942,344, filed on Nov. 16, 2015, which is a continuation-in-partapplication of Ser. No. 14/659,472, filed on Mar. 16, 2015, now U.S.Pat. No. 9,211,253, which claims benefit of Ser. No. 61/953,379, filedon Mar. 14, 2014. This application also claims benefit of Ser. No.62/219,955, filed on 17 Sep. 2015 and Ser. No. 62/274,536, filed on 4Jan. 2016. The entire disclosures of the applications identified in thisparagraph are incorporated herein by references.

JOINT RESEARCH AGREEMENT

The subject matter disclosed and claimed herein was developed by or onbehalf of LightLake Therapeutics Inc. and Adapt Pharma Operations Ltd.,as parties to a joint research agreement, and as a result of activitiesundertaken within the scope of the joint research agreement. The jointresearch agreement was in effect on or before the effective filing dateof the present claims.

FIELD

This disclosure generally relates to pharmaceutical compositionscomprising an opioid receptor antagonist, medical devices for deliveryof the pharmaceutical compositions, and methods of using thecompositions and the medical devices.

BACKGROUND

This section provides background information related to the presentdisclosure which is not necessarily prior art.

Opioid receptors are G protein-coupled receptors (GPCRs) that areactivated both by endogenous opioid peptides and by clinically importantalkaloid analgesic drugs such as morphine. There are three principaltypes of opioid receptors: the δ-opioid receptor, the κ-opioid receptor,and the μ-opioid receptor. Opioids depress respiration, which iscontrolled principally through medullary respiratory centers withperipheral input from chemoreceptors and other sources. Opioids produceinhibition at the chemoreceptors via μ-opioid receptors and in themedulla via μ- and δ-opioid receptors. While there are a number ofneurotransmitters mediating the control of respiration, glutamate andγ-aminobutyric acid (GABA) are the major excitatory and inhibitoryneurotransmitters, respectively. Oxycodone and other opioid painkillers,as well as heroin and methadone are all implicated in fatal overdose.

In the United States, mortality rates closely correlate with opioidsales. In 2014, there were 47,055 drug overdose deaths in the UnitedStates, representing a 6.5% increase from 2013 as reported by Rudd etal. (2016) Morbidity & Mortality Weekly Report 64(50):1378-82 (startingat page 10) “Increases in Drug and Opioid Overdose Deaths—United States,2000-2014.” Over 28,000 of those were overdoses of heroin orprescription opioids, which represents nearly a four-fold increase since1999. Drugs classed as prescription opioids include both typicalanalgesics, such as OxyContin® (oxycodone HCl controlled-release) andmethadone (used in the treatment of dependence on other opioids such asheroin and also prescribed for pain), but the increase in the rate ofdrug overdose in recent years has been driven mainlyby overdoses ofprescription analgesics.

Naloxone is an opioid receptor antagonist that is approved for use byinjection for the reversal of opioid overdose and for adjunct use in thetreatment of septic shock. It is currently being used mainly inemergency departments and in ambulances by trained medicalprofessionals. There have been efforts to expand its use by providingthe drug to some patients with take-home opioid prescriptions and thosewho inject illicit drugs, potentially facilitating earlieradministration of the drug.

U.S. Pat. No. 4,464,378 to Hussain reports a method for eliciting ananalgesic or narcotic antagonist response in a warm-blooded animal,which comprises administering intranasally (IN) to said animal to elicita narcotic antagonist response, a narcotic antagonist effective amountof naloxone.

WO 82/03768 to Hussain reports a composition that contains 1 mg ofnaloxone hydrochloride per 0.1 ml of solution adapted for nasaladministration used in the treatment of narcotic induced respiratorydepression (overdose) at a dosage approximately the same as thatemployed for intravenous (IV), intramuscular (IM) or subcutaneous (SQ)administration.

WO 00/62757 to Davies reports pharmaceutical compositions for IN or oral(PO) administration which comprise an opioid antagonist, such asnaloxone for application by spray in the reversal of opioid depressionfor treatment of patients suffering from opioid over-dosage, wherein thespray applicator is capable of delivering single or multiple doses andsuitable dosage units are in the range of 0.2 to 5 mg.

The use of nasal naloxone is not without controversy. For instance,Dowling et al. (Ther Drug Monit, Vol 30, No 4, August 2008) reportedthat naloxone administered intranasally displays a relativebioavailability of 4% only and concluded that the IN absorption is rapidbut does not maintain measurable concentrations for more than an hour.

U.S. Pat. No. 9,192,570 to Wyse reports naloxone formulations forintranasal administration. Wyse reports (column 27, lines 29-37) thatbenzalkonium chloride is not suitable in such formulations, because itfacilitates unacceptable degradation of the naloxone. Wyse recommends(lines 41-43) benzyl alcohol and paraben preservatives in place ofbenzalkonium chloride.

Thus, there remains a need for durable, easy-to-use, needleless deviceswith storage-stable formulations, that can enable untrained individualsto quickly deliver a therapeutically effective dose of a rapid-actingopioid antagonist to an opioid overdose patient. The therapeuticallyeffective dose should be sufficient to obviate the need for theuntrained individual to administer an alternative medical interventionto the patient, and to stabilize the patient until professional medicalcare becomes available.

SUMMARY

This section provides a general summary of the disclosure, and is not acomprehensive disclosure of its full scope or all of its features.

This disclosure provides an improved single-use, pre-primed deviceadapted for nasal delivery of a pharmaceutical solution to a patientcomprising: at least about 4% (w/v) naloxone hydrochloride or a hydratethereof, wherein the improvement comprises that the device is adapted tospray a round plume with an ovality ratio less than about 2, for exampleless than about 1.5.

In another embodiment, there is provided a mist comprising droplets ofan at least 4% (w/v) naloxone hydrochloride solution, wherein no morethan about 10%, for example no more than about 5%, of the droplets havea diameter less than 10 μm.

In yet another embodiment, there is provided an improved single-use,pre-primed device adapted for nasal delivery of a pharmaceuticalsolution to a patient comprising: at least about 4% (w/v) naloxonehydrochloride or a hydrate thereof; and between about 0.2% and about1.2% (w/v) of an isotonicity agent, wherein the improvement comprisesthat the device is adapted to spray a round plume with an ovality ratioless than about 2.0.

In yet another embodiment, there is provided an improved single-use,pre-primed device adapted for nasal delivery of a pharmaceuticalsolution to a patient comprising: at least about 4% (w/v) naloxonehydrochloride or a hydrate thereof; and between about 0.005% and about0.015% (w/v) of a preservative, wherein the improvement comprises thatthe device is adapted to spray a round plume with an ovality ratio lessthan about 2.0.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the mean (±SD) naloxone plasma concentration followingadministration of 0.4 mg intramuscular (IM), 2 mg intranasal (IN), and 4mg IN in 14 human subjects.

FIG. 2 shows the mean (±SD) naloxone plasma concentration withlogarithmic transformation following administration of 0.4 mgintramuscular (IM), 2 mg intranasal (IN), and 4 mg IN in 14 humansubjects.

FIG. 3 shows the mean naloxone plasma concentration following singleintranasal administrations (FIG. 3A) and intramuscular injections (FIG.3B) of naloxone to healthy subjects (N=28) over a twelve-hour period.

FIG. 4 shows the mean naloxone plasma concentration following singleintranasal administrations (FIG. 4A) and intramuscular injections (FIG.4B) of naloxone to healthy subjects (N=28) over a four-hour period.

FIG. 5 shows the mean naloxone plasma concentration followingintramuscular injection of 0.4 mg naloxone (FIG. 5A, top) and one sprayof 20 mg/mL (i.e., 2% w/v) naloxone (FIG. 5B, bottom) to healthy male(N=16) and female (N=12) subjects over a twelve-hour period.

FIG. 6 shows the mean naloxone plasma concentration following two spraysof 20 mg/mL (i.e., 2% w/v, FIG. 6A, top) and one spray of 40 mg/mL(i.e., 4% w/v, FIG. 6B, bottom) to healthy male (N=16) and female (N=12)subjects over a twelve-hour period.

FIG. 7 shows the mean naloxone plasma concentration following two spraysof 40 mg/mL (i.e., 4% w/v) to healthy male (N=16) and female (N=12)subjects over a twelve-hour period.

DETAILED DESCRIPTION

Definition

For clarity and consistency, the following definitions will be usedthroughout this patent document.

The term “active ingredient” or “pharmaceutically active compound” isdefined in the context of a “pharmaceutical composition” and is intendedto mean a component of a pharmaceutical composition that provides theprimary pharmacological effect, as opposed to an “inactive ingredient”which would generally be recognized as providing no pharmaceuticalbenefit.

The term “actuation,” as used herein, refers to operation of the devicesuch that the pharmaceutical composition is delivered therefrom.

The term “agonist,” as used herein, refers to as used herein refers to amoiety that interacts with and activates a receptor, and therebyinitiates a physiological or pharmacological response characteristic ofthat receptor. The term “antagonist,” as used herein, refers to a moietythat competitively binds to a receptor at the same site as an agonist(for example, the endogenous ligand), but which does not activate theintracellular response initiated by the active form of the receptor andcan thereby inhibit the intracellular responses by an agonist or partialagonist. An antagonist does not diminish the baseline intracellularresponse in the absence of an agonist or partial agonist. The term“inverse agonist” refers to a moiety that binds to the endogenous formof the receptor or to the constitutively activated form of the receptorand which inhibits the baseline intracellular response initiated by theactive form of the receptor below the normal base level of activitywhich is observed in the absence of an agonist or partial agonist.

The term “antimicrobial preservative,” as used herein, refers to apharmaceutically acceptable excipient with antimicrobial propertieswhich is added to a pharmaceutical composition to maintainmicrobiological stability.

The term “AUC,” as used herein, refers to the area under the drug plasmaconcentration-time curve. The term “AUC_(0-t),” as used herein, refersto the area under the drug plasma concentration-time curve from t=0 tothe last measurable concentration. The term “AUC_(0-∞),” as used herein,refers to the area under the drug plasma concentration-time curveextrapolated to ∞. The term “AUC_(0-t/D),” as used herein, refers to theAUC_(0-t) normalized to 0.4 mg IM naloxone. The term “AUC_(0-∞/D),” asused herein, refers to the AUC_(0-∞) normalized to 0.4 mg IM naloxone

The term “bioavailability (F),” as used herein, refers to the fractionof a dose of drug that is absorbed from its site of administration andreaches, in an unchanged form, the systemic circulation. The term“absolute bioavailability” is used when the fraction of absorbed drug isrelated to its IV bioavailability. It may be calculated using thefollowing formula:

$F = {\frac{{AUC}_{extravascular}}{{AUC}_{intravenous}} \times \frac{{Dose}_{intravenous}}{{Dose}_{extravascular}}}$The term relative bioavailability (F_(rel)) is used to compare twodifferent extravascular routes of drug administration and it may becalculated using the following formula:

$F_{rel} = {\frac{{AUC}_{{extravascular}\mspace{11mu} 1}}{{AUC}_{{extravascular}\mspace{11mu} 2}} \times \frac{{Dose}_{{extravascular}\mspace{11mu} 2}}{{Dose}_{{extravascular}\mspace{11mu} 1}}}$

The term “clearance (CL),” as used herein, refers to the rate at which adrug is eliminated divided by its plasma concentration, giving a volumeof plasma from which drug is completely removed per unit of time. CL isequal to the elimination rate constant (λ) multiplied by the volume ofdistribution (V_(d)), wherein “V_(d)” is the fluid volume that would berequired to contain the amount of drug present in the body at the sameconcentration as in the plasma. The term “apparent clearance (CL/F),” asused herein, refers to clearance that does not take into account thebioavailability of the drug. It is the ratio of the dose over the AUC.

The term “C_(max),” as used herein, refers to the maximum observedplasma concentration. The term “C_(max/D),” as used herein, refers toC_(max) normalized to 0.4 mg IM naloxone.

The term “coefficient of variation (CV),” as used herein, refers to theratio of the sample standard deviation to the sample mean. It is oftenexpressed as a percentage.

The term “confidence interval,” as used herein, refers to a range ofvalues which will include the true average value of a parameter aspecified percentage of the time.

The term “device,” as used herein, refers to an apparatus capable ofdelivering a drug to patient in need thereof.

The term “delivery time,” as used herein, refers to the amount of timethat elapses between a determination made by a healthcare professional,or an untrained individual that an individual is in need of nasaldelivery of an opioid antagonist and completion of the delivery.

The term “elimination rate constant (λ),” as used herein, refers to thefractional rate of drug removal from the body. This rate is constant infirst-order kinetics and is independent of drug concentration in thebody. λis the slope of the plasma concentration-time line (on alogarithmic y scale). The term “λ_(z),” as used herein, refers to theterminal phase elimination rate constant, wherein the “terminal phase”of the drug plasma concentration-time curve is a straight line whenplotted on a semilogarithmic graph. The terminal phase is often calledthe “elimination phase” because the primary mechanism for decreasingdrug concentration during the terminal phase is drug elimination fromthe body. The distinguishing characteristic of the terminal eliminationphase is that the relative proportion of drug in the plasma andperipheral volumes of distribution remains constant. During this“terminal phase” drug returns from the rapid and slow distributionvolumes to the plasma, and is permanently removed from the plasma bymetabolism or renal excretion.

The term “equivalent,” as used herein refers to a weight of an opioidantagonist selected from naloxone and pharmaceutically acceptable saltsthereof that is equimolar to a specified weight of naloxonehydrochloride. For example, 8 mg of anhydrous naloxone hydrochloride(molecular weight, 363.84) is equivalent to about 7.2 mg of naloxonefreebase (molecular weight, 327.37), and to about 8.8 mg of naloxonehydrochloride dihydrate (molecular weight 399.87).

The term “filled,” as used herein, refers to an association between adevice and a pharmaceutical composition, for example, when apharmaceutical composition described herein comprising a therapeuticallyeffective amount of an opioid antagonist is present within a reservoirthat forms a part of a device described herein.

The term “hydrate,” as used herein, refers to an opioid antagonistdescribed herein or a salt thereof that further includes astoichiometric or non-stoichiometric amount of water bound bynon-covalent intermolecular forces.

The term “in need of treatment” and the term “in need thereof” whenreferring to treatment are used interchangeably and refer to a judgmentmade by a caregiver (e.g. physician, nurse, nurse practitioner) that apatient will benefit from treatment.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein the amount of naloxone hydrochloride is specifiedto be 4 mg is mutually exclusive with an embodiment wherein the amountof naloxone hydrochloride is specified to be 2 mg. However, anembodiment wherein the amount of naloxone hydrochloride is specified tobe 4 mg is not mutually exclusive with an embodiment in which less thanabout 10% of said pharmaceutical composition leaves the nasal cavity viadrainage into the nasopharynx or externally.

The term “naloxone,” as used herein, refers to a compound of thefollowing structure:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof. TheCAS registry number for naloxone is 465-65-6. Other names for naloxoneinclude: 17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one;(−)-17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-one;4,5a-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; and(−)-12-allyl-7,7a,8,9-tetrahydro-3,7a-dihydroxy-4aH-8,9c-iminoethanophenanthro[4,5-bcd]furan-5(6H)-one.Naloxone hydrochloride may be anhydrous (CAS Reg. No. 357-08-4) and alsoforms a dihydrate (CAS No. 51481-60-8). It has been sold under variousbrand names including Narcan®, Nalone®, Nalossone®, Naloxona®,Naloxonum®, Narcanti®, and Narcon®.

The term “nostril,” as used herein, is synonymous with “naris.”

The term “opioid antagonist” includes, in addition to naloxone andpharmaceutically acceptable salts thereof: naltrexone, methylnaltrexone,and nalmefene, and pharmaceutically acceptable salts thereof. In someembodiments, the opioid antagonist is naloxone hydrochloride. In someembodiments, the opioid antagonist is naloxone hydrochloride dihydrate.In some embodiments, the opioid antagonist is naltrexone hydrochloride.In some embodiments, the opioid antagonist is methylnaltrexone bromide.In some embodiments, the opioid antagonist is nalmefene hydrochloride.In some embodiments, the nasally administering is accomplished using adevice described herein.

The term “opioid overdose,” as used herein, refers to an acute medicalcondition induced by excessive use of one or more opioids. Symptoms ofopioid overdose include including respiratory depression, centralnervous system depression (which may include sedation, altered levelconsciousness, miotic (constricted) pupils), and cardiovasculardepression (which may include hypoxemia and hypotension). Visible signsof opioid overdose or suspected opioid overdose include:unresponsiveness and/or loss of consciousness (won't respond to stimulisuch as shouting, shaking, or rubbing knuckles on sternum); slow,erratic, or stopped breathing; slow, erratic, or stopped pulse; deepsnoring or choking/gurgling sounds; blue or purple fingernails or lips;pale and/or clammy face; slack or limp muscle tone; contracted pupils;and vomiting. Because opioid overdose may be difficult to diagnoseand/or quantify, particularly by a lay person, as used herein, treatmentof opioid overdose is meant to include treatment of suspected opioidoverdose in opioid-intoxicated patients. Opioids that may induceoverdose include, codeine, morphine, methadone, fentanyl, oxycodone HCl,hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine,propoxyphene, opium, heroin, tramadol, tapentadol, and certainnarcotic-antagonist analgesics, such as, nalbuphine, pentazocine andbutorphanol. In some embodiments, the opioid agonist is in atamper-proof formulation. In some embodiments, the opioid agonist is ina tamper-resistant formulation. In some embodiments, the opioid agonistis selected from Acurox® Oxycodone DETERx®, Oxycontin®, Egalethydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®, Opana®ER, Vicodin®, Percocet® and Remoxy®.

The term “patient,” as used herein, refers to any subject (preferablyhuman) afflicted with a condition likely to benefit from a treatmentwith a therapeutically effective amount of an opioid antagonist.

The terms “permeation enhancer” and “penetration enhancer,” as disclosedherein, are intended to be equivalent, both referring to an agent whichaids in absorption of a compound, such as through the nasal mucosa.

The term “pharmaceutical composition,” as used herein, refers to acomposition comprising at least one active ingredient; including but notlimited to, salts, solvates and hydrates of the opioid antagonistsdescribed herein, whereby the composition is amenable to use for aspecified, efficacious outcome in a mammal (for example, withoutlimitation, a human).

The term “pre-primed,” as used herein, refers to a device, such as anasal spray which is capable of delivering a pharmaceutical compositionto a patient in need thereof with the first actuation of the spray pump,i.e., without the need to prime the pump prior to dosing, such as byactuating the pump one or more times until a spray appears.

The term “receptor binding or occupancy” refers to a characterization ofthe kinetics between a radioactive drug and receptors or other bindingsites throughout the body, and characterization of the radioactive drugbinding affinity to these receptors.

The term “recovery position,” as used herein, means a position of thehuman body in which a patient lies on his/her side, with a leg or kneeout in front (e.g., to prevent rolling onto his/her stomach) and atleast one hand supporting the head (e.g., to elevate the face tofacilitate breathing and prevent inhalation of vomit).

The term “solvate,” as used herein, refers to an opioid antagonistdescribed herein or a salt, thereof, that further includes astoichiometric or non-stoichiometric amount of a solvent bound bynon-covalent intermolecular forces. Preferred solvents are volatile,non-toxic, and/or acceptable for administration to humans in traceamounts.

The term “sterile filling,” as used herein, refers methods ofmanufacturing the devices and pharmaceutical compositions describedherein, such that the use of preservatives is not required. Sterile drugproducts may be produced using aseptic processing or terminalsterilization. Terminal sterilization usually involves filling andsealing product containers under high-quality environmental conditions.In an aseptic process, the drug product, container, and closure arefirst subjected to sterilization methods separately, as appropriate, andthen brought together.

The term “storage-stable,” as used herein, refers to a pharmaceuticalcomposition in which at least about 95%—for example at least about99.5%—of the active ingredient remains in an undegraded state afterstorage of the pharmaceutical composition at specified temperature andhumidity for a specified time, for example, for 12 months at 25° C. and60% relative humidity.

The term “supine,” as used herein, refers to a patient who is lying faceup.

The term “t_(1/2)” or “half-life,” as used herein, refers to the amountof time required for half of a drug to be eliminated from the body orthe time required for a drug concentration to decline by half.

The term “tonicity agent,” as used herein, refers to a compound whichmodifies the osmolality of a formulation, for example, to render itisotonic. Tonicity agents include, dextrose, lactose, sodium chloride,calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol,trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycineand the like.

The term “tomography,” as used herein, refers to a process of imaging bysections. The images may be looked at individually, as a series oftwo-dimensional slices or together, as a computer-generatedthree-dimensional representation.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent of a pharmaceutical composition that it compatible with theother ingredients of the formulation and not overly deleterious to therecipient thereof.

The term “substantially free of antimicrobial preservatives” isunderstood by one of ordinary skill in the art to describe apharmaceutical composition that may comprise less than 1% w/wantimicrobial preservatives.

The term “therapeutically effective amount,” as used herein, refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, or individual thatis being sought by a researcher, healthcare provider or individual.

The term “t_(max),” as used herein, refers to the time fromadministration of the pharmaceutical compositions described herein tomaximum drug plasma concentration.

The term “untrained individual” refers to an individual administering topatient an opioid antagonist using a device described herein, whereinthe individual is not a healthcare professional and has received littleor no training in the use of the device, such as through an overdoseeducation and nasal naloxone distribution (OEND) program.

Where definitions conflict as between the present text and textsincorporated by reference, the definitions of the present text control.

Opioid Antagonists

Provided are drug products adapted for nasal delivery of an opioidreceptor antagonist. Opioid receptor antagonists are a well recognizedclass of chemical agents. They have been described in detail in thescientific and patent literature. Pure opioid antagonists, such asnaloxone, are agents which specifically reverse the effects of opioidagonists but have no opioid agonist activity.

Naloxone is commercially available as a hydrochloride salt. Naloxonehydrochloride (17-allyl-4,5a-epoxy-3,14-dihydroxymorphinan-6-onehydrochloride), a narcotic antagonist, is a synthetic congener ofoxymorphone. In structure it differs from oxymorphone in that the methylgroup on the nitrogen atom is replaced by an allyl group. Naloxonehydrochloride is an essentially pure narcotic antagonist, i.e., it doesnot possess the “agonistic” or morphine-like properties characteristicof other narcotic antagonists; naloxone does not produce respiratorydepression, psychotomimetic effects or pupillary constriction. In theabsence of narcotics or agonistic effects of other narcotic antagonistsit exhibits essentially no pharmacologic activity. Naloxone has not beenshown to produce tolerance or to cause physical or psychologicaldependence. In the presence of physical dependence on narcotics naloxonewill produce withdrawal symptoms.

While the mechanism of action of naloxone is not fully understood, thepreponderance of evidence suggests that naloxone antagonizes the opioideffects by competing for the same receptor sites. When naloxonehydrochloride is administered intravenously the onset of action isgenerally apparent within two minutes; the onset of action is onlyslightly less rapid when it is administered subcutaneously orintramuscularly. The duration of action is dependent upon the dose androute of administration of naloxone hydrochloride. Intramuscularadministration produces a more prolonged effect than intravenousadministration. The requirement for repeat doses of naloxone, however,will also be dependent upon the amount, type and route of administrationof the narcotic being antagonized. Following parenteral administrationnaloxone hydrochloride is rapidly distributed in the body. It ismetabolized in the liver, primarily by glucuronide conjugation, andexcreted in urine. In one study the serum half-life in adults rangedfrom 30 to 81 minutes (mean 64±12 minutes). In a neonatal study the meanplasma half-life was observed to be 3.1±0.5 hours.

Provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the device is pre-primed, and whereinthe therapeutically effective amount, is equivalent to about 2 mg toabout 12 mg of naloxone hydrochloride. Also provided are devices adaptedfor nasal delivery of a pharmaceutical composition to a patient,comprising a therapeutically effective amount of an opioid antagonistselected from naloxone and pharmaceutically acceptable salts thereof,wherein the device is pre-primed, and wherein the therapeuticallyeffective amount, is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 2 mg to about 24 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 2 mg to about 12 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3 mg to about 18 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg to about 10mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 5 mg to about 11 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 6 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments,the therapeutically effective amount is equivalent to about 7 mg toabout 9 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 3.4 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 5 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 6 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 7 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about8 mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 9 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 10 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 11 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 12 mg of naloxone hydrochloride.In some embodiments, the opioid antagonist is the only pharmaceuticallyactive compound in pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, theopioid antagonist is anhydrous naloxone hydrochloride. In someembodiments, the opioid antagonist is naloxone hydrochloride dihydrate.

While many of the embodiments of the pharmaceutical compositionsdescribed herein will be described and exemplified with naloxone, otheropioid antagonists can be adapted for nasal delivery based on theteachings of the specification. In fact, it should be readily apparentto one of ordinary skill in the art from the teachings herein that thedevices and pharmaceutical compositions described herein may be suitablefor other opioid antagonists. The opioid receptor antagonists describedherein include μ-opioid antagonists and δ-opioid receptor antagonists.Examples of useful opioid receptor antagonists include naloxone,naltrexone, methylnaltrexone, and nalmefene. Other useful opioidreceptor antagonists are known (see, e.g., Kreek et al., U.S. Pat. No.4,987,136).

Also provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist, wherein the device is pre-primed, and whereinthe therapeutically effective amount is about 4 mg to about 12 mg. Insome embodiments, the therapeutically effective amount is equivalent toabout 3.4 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, the opioid antagonist is selectedfrom naltrexone, methylnaltrexone, and nalmefene, and pharmaceuticallyacceptable salts thereof. In some embodiments, the opioid antagonist isnaltrexone hydrochloride. In some embodiments, the opioid antagonist ismethylnaltrexone bromide. In some embodiments, the opioid antagonist isnalmefene hydrochloride. In some embodiments, the opioid antagonist isthe only pharmaceutically active compound in pharmaceutical composition.

Nasal Drug Delivery Devices and Kits

Also provided are nasal drug delivery devices comprising apharmaceutical composition described herein. Nasal delivery isconsidered an attractive route for needle-free, systemic drug delivery,especially when rapid absorption and effect are desired. In addition,nasal delivery may help address issues related to poor bioavailability,slow absorption, drug degradation, and adverse events (AEs) in thegastrointestinal tract and avoids the first-pass metabolism in theliver.

Liquid nasal formulations are mainly aqueous solutions, but suspensionsand emulsions can also be delivered. In traditional spray pump systems,antimicrobial preservatives are typically required to maintainmicrobiological stability in liquid formulations.

Some emergency medical services (EMS) programs have developed a systemusing existing technologies of an approved drug and an existing medicaldevice to administer naloxone intranasally, albeit in a non-FDA approvedmanner. This has been accomplished by using the injectable formulation(1 mg/mL) and administering 1 mL per nostril via a marketed nasalatomizer/nebulizer device. The system combines an FDA-approved naloxoneinjection product (with a Luer fitted tip, no needles) with a marketed,medical device called the Mucosal Atomization Device (MAD™ Nasal, WolfeTory Medical, Inc.). The EMS programs recognize limitations of thissystem, one limitation being that it is not assembled and ready-to-use.Although this administration mode appears to be effective in reversingnarcosis, the formulation is not concentrated for retention in the nasalcavity. The human nasal cavity has a volume of ˜200-250 μL. The 1 mLdelivery volume per nostril is larger than that generally utilized forintranasal drug administration. Therefore, there is loss of drug fromthe nasal cavity, due either to drainage into the nasopharynx orexternally from the nasal cavity. The devices described herein areimproved ready-to-use products specifically optimized, concentrated, andformulated for nasal delivery.

Metered spray pumps have dominated the nasal drug delivery market sincethey were introduced. The pumps typically deliver 100 μL (25-200 μL) perspray, and they offer high reproducibility of the emitted dose and plumegeometry in in vitro tests. The particle size and plume geometry canvary within certain limits and depend on the properties of the pump, theformulation, the orifice of the actuator, and the force applied.Traditional spray pumps replace the emitted liquid with air, andpreservatives are therefore required to prevent contamination. However,driven by the studies suggesting possible negative effects ofpreservatives, pump manufacturers have developed different spray systemsthat avoid the need for preservatives. These systems use a collapsiblebag, a movable piston, or a compressed gas to compensate for the emittedliquid volume (www.aptar.com and www.rexam.-com). The solutions with acollapsible bag and a movable piston compensating for the emitted liquidvolume offer the additional advantage that they can be emitted upsidedown, without the risk of sucking air into the dip tube and compromisingthe subsequent spray. This may be useful for some products where thepatients are bedridden and where a head down application is recommended.Another method used for avoiding preservatives is that the air thatreplaces the emitted liquid is filtered through an aseptic air filter.In addition, some systems have a ball valve at the tip to preventcontamination of the liquid inside the applicator tip (www.aptar.com).More recently, pumps have been designed with side-actuation andintroduced for delivery of fluticasone furoate for the indication ofseasonal and perennial allergic rhinitis. The pump was designed with ashorter tip to avoid contact with the sensitive mucosal surfaces. Newdesigns to reduce the need for priming and re-priming, and pumpsincorporating pressure point features to improve the dosereproducibility and dose counters and lock-out mechanisms for enhanceddose control and safety are available (www.rexam.com and www.aptar.com).

Metered-dose spray pumps require priming and some degree of overfill tomaintain dose conformity for the labeled number of doses. They are wellsuited for drugs to be administered daily over a prolonged duration, butdue to the priming procedure and limited control of dosing, they areless suited for drugs with a narrow therapeutic window. For expensivedrugs and vaccines intended for single administration or sporadic useand where tight control of the dose and formulation is of particularimportance, single-dose or bi-dose spray devices are preferred(www.aptar.com). A simple variant of a single-dose spray device (MAD™)is offered by LMA (LMA, Salt Lake City, Utah, USA; www.lmana.com). Anosepiece with a spray tip is fitted to a standard syringe. The liquiddrug to be delivered is first drawn into the syringe and then the spraytip is fitted onto the syringe. This device has been used in academicstudies to deliver, for example, a topical steroid in patients withchronic rhinosinusitis and in a vaccine study. A pre-filled device basedon the same principle for one or two doses (Accuspray™, Becton DickinsonTechnologies, Research Triangle Park, N.C., USA; www.bdpharma.com) isused to deliver the influenza vaccine FluMist (www.flumist.com),approved for both adults and children in the US market. A similar devicefor two doses was marketed by a Swiss company for delivery of anotherinfluenza vaccine a decade ago. The single- and bi-dose devicesmentioned above consist of a reservoir, a piston, and a swirl chamber(see, e.g., the UDS UnitDose and BDS BiDose devices from Aptar, formerlyPfeiffer). The spray is formed when the liquid is forced out through theswirl chamber. These devices are held between the second and the thirdfingers with the thumb on the actuator. A pressure point mechanismincorporated in some devices secures reproducibility of the actuationforce and emitted plume characteristics. Currently, marketed nasalmigraine drugs like Imitrex (www.gsk.com) and Zomig (www.az.com;Pfeiffer/Aptar single-dose device) and the marketed influenza vaccineFlu-Mist (www.flumist.com; Becton Dickinson single-dose spray device)are delivered with this type of device.

With sterile filling, the use of preservatives is not required, butoverfill is required resulting in a waste fraction similar to themetered-dose, multi-dose sprays. To emit 100 μL, a volume of 125 μL isfilled in the device (Pfeiffer/Aptar single-dose device) used for theintranasal migraine medications Imitrex (sumatriptan) and Zomig(zolmitriptan) and about half of that for a bi-dose design. Sterile drugproducts may be produced using aseptic processing or terminalsterilization. Terminal sterilization usually involves filling andsealing product containers under high-quality environmental conditions.Products are filled and sealed in this type of environment to minimizethe microbial and particulate content of the in-process product and tohelp ensure that the subsequent sterilization process is successful. Inmost cases, the product, container, and closure have low bioburden, butthey are not sterile. The product in its final container is thensubjected to a sterilization process such as heat or irradiation. In anaseptic process, the drug product, container, and closure are firstsubjected to sterilization methods separately, as appropriate, and thenbrought together. Because there is no process to sterilize the productin its final container, it is critical that containers be filled andsealed in an extremely high-quality environment. Aseptic processinginvolves more variables than terminal sterilization. Before asepticassembly into a final product, the individual parts of the final productare generally subjected to various sterilization processes. For example,glass containers are subjected to dry heat; rubber closures aresubjected to moist heat; and liquid dosage forms are subjected tofiltration. Each of these manufacturing processes requires validationand control.

Accordingly, provided herein are devices adapted for nasal delivery of apharmaceutical composition to a patient, comprising a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein said device ispre-primed, and wherein said therapeutically effective amount, isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride.

In some embodiments, said opioid antagonist is naloxone hydrochloride.In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual. Also disclosedherein are methods of improving accuracy of dose delivery by anuntrained individual, the method comprising administering a dose ofopioid antagonist from a device as described herein.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg to about 10 mg of naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent to anamount chosen from about 2 mg naloxone hydrochloride, about 4 mgnaloxone hydrochloride, and about 8 mg naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent toabout 2 mg of naloxone hydrochloride. In some embodiments, saidtherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, said therapeutically effectiveamount is equivalent to about 8 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3.4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, said therapeutically effective amount is about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, said therapeutically effective amount isabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, said therapeuticallyeffective amount is about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said pharmaceutical composition comprises asolution of naloxone hydrochloride, or a hydrate thereof.

In some embodiments, the volume of said pharmaceutical composition insaid reservoir is not more than about 140 μL.

In some embodiments, about 100 μL of said pharmaceutical composition insaid reservoir is delivered to said patient in one actuation.

In some embodiments, said pharmaceutical composition further comprisesone or more excipients selected from water and NaCl.

In some embodiments, said pharmaceutical composition is substantiallyfree of antimicrobial preservatives.

In some embodiments, said pharmaceutical composition further comprises apreservative, permeation/penetration enhancer and/or a cationicsurfactant; an isotonicity agent; a stabilizing agent; and an amount ofacid sufficient to achieve a pH of 3.5-5.5. In some embodiments, thepreservative, permeation/penetration enhancer and/or a cationicsurfactant is selected from benzalkonium chloride, cyclodextrins,fusidic acid derivatives, phosphatidylcholines, microspheres andliposomes, and bile salts. In a particular embodiment, the preservative,permeation/penetration enhancer and/or a cationic surfactant isbenzalkonium chloride.

In some embodiments, said pharmaceutical composition further comprisesone or more excipients selected from water, NaCl, benzalkonium chloride,sodium edetate, disodium edetate, and hydrochloric acid.

In some embodiments, said pharmaceutical composition further compriseswater, NaCl, benzalkonium chloride, disodium edetate, and hydrochloricacid.

In certain embodiments, said pharmaceutical composition comprisesbenzalkonium chloride. The can function as a preservative (even in lowamounts), a permeation/penetration enhancer, and/or a cationicsurfactant (typically at a higher amount for these latter two).Benzalkonium chloride is represented by the following structure:

in which n is an integer, and a mixture of more than one thereof can beused. In certain embodiments, n is 8, 10, 12, 14, 16, or 18, and incertain embodiments, n is 10, 12, or 14. In certain embodiments, saidpharmaceutical composition comprises about 0.005% to about 1%benzalkonium chloride. In certain embodiments, said pharmaceuticalcomposition comprises about 0.01% to about 1% benzalkonium chloride. Incertain embodiments, said pharmaceutical composition comprises about0.005% to about 0.015% benzalkonium chloride.

In its capacity as a surfactant, benzalkonium chloride can affect thesurface tension of droplets from a delivered nasal spray plume,producing spherical or substantially spherical particles having a narrowdroplet size distribution (DSD), as well as the viscosity of a liquidformulation.

The droplet size distribution of a nasal spray is a critical parameter,since it significantly influences the in vivo deposition of the drug inthe nasal cavity. The droplet size is influenced by the actuationparameters of the device and the formulation. The prevalent mediandroplet size should be between about 30 and about 100 μm. If thedroplets are too large (>about 120 μm), deposition takes place mainly inthe anterior parts of the nose, and if the droplets are too small(<about 10 μm), they can possibly be inhaled and reach the lungs, whichshould be avoided because of safety reasons (benzalkonium chloridesignificantly increases mucin secretion while significantly attenuatingmucoiliary transport rate and is toxic to 16HBE14o-cells.)

Spray characterization (e.g., plume geometry, spray pattern, pumpdelivery, droplet size distribution, DSD) of the delivered plumesubsequent to spraying may be measured under specified experimental andinstrumental conditions by appropriate and validated and/or calibratedanalytical procedures known in the art. These include photography, laserdiffraction, and impaction systems (cascade impaction, next generationimpaction (NGI), etc.). Droplet size distribution can be controlled interms of ranges for the D10, D50, D90, span [(D90−D10)/D50], andpercentage of droplets less than 10 mm. In certain embodiments, theformulation will have a narrow DSD. In certain embodiments, theformulation will have a Dv(50) of 30-70 μm and a Dv(90)<100 μm. Theparticle diameter “(D)” designations refer to the representativediameter where 10% (D10), 50% (D50) and 90% (D90) of the total volume ofthe liquid sprayed is made up of droplets with diameters smaller than orequal to the stated value.

In certain embodiments, the percent of droplets less than 10 μm will beless than 10%. In certain embodiments, the percent of droplets less than10 μm will be less than 5%. In certain embodiments, the percent ofdroplets less than 10 μm will be less than 2%. In certain embodiments,the percent of droplets less than 10 μm will be less than 1%. In certainembodiments, the spray—also described at times as a “mist”—having thesedroplet size characteristics can comprise a preservative composed of oneor more compounds of formula (I)

wherein n is an integer selected from the group consisting of 8, 10, 12,14, 16, and 18. For example, n can be an integer selected from the groupconsisting of 10, 12, and 14.

In certain embodiments, the formulation when dispensed by actuation fromthe device will produce a uniform circular spray plume with an ovalityratio close to 1. In certain embodiments, the ovality ratio is between0.7 and 2.5. In certain embodiments, the ovality ratio is less than 2.0.In certain embodiments, the ovality ratio is less than 1.5. In certainembodiments, the ovality ratio is less than 1.3. In certain embodiments,the ovality ratio is less than 1.2. In certain embodiments, the ovalityratio is less than 1.1. In certain embodiments, the ovality ratio isabout 1.0.

When benzalkonium chloride is provided in a formulation in an amounteffective to function as a permeation/penetration enhancer and/or acationic surfactant, the spray pattern, droplet size and DSD areexpected to provide improved pharmacokinetic outcomes such as C_(max),t_(max), and linear dose proportionality compared to both intramuscularformulations and intranasal formulations that do not containbenzalkonium chloride in an amount effective to function as apermeation/penetration enhancer and/or a cationic surfactant. In certainembodiments, a formulation as disclosed herein comprising benzalkoniumchloride in an amount effective to function as a permeation/penetrationenhancer and/or a cationic surfactant will yield a formulation that isat least 35% bioavailable, at least 40% bioavailable, at least 45%bioavailable, at least 50% bioavailable, or at least 55% bioavailable.

Accordingly, provided herein is a drug product comprising a combinationof a therapeutically effective amount of an opioid agonist and atherapeutically effective amount of naloxone hydrochloride or a hydratethereof, wherein said naloxone hydrochloride or hydrate thereof iscontained in a single-use, pre-primed device adapted for nasal deliveryof a pharmaceutical composition to a patient by one actuation of saiddevice into one nostril of said patient, and wherein the single-use,pre-primed device comprises a reservoir containing a pharmaceuticalcomposition which is an aqueous solution of about 100 μL comprising:

-   -   naloxone hydrochloride or a hydrate thereof;    -   benzalkonium chloride in an amount effective to function as a        permeation/penetration enhancer and/or a cationic surfactant;    -   an isotonicity agent;    -   a stabilizing agent; and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments, the single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient comprisesbetween about 2 mg and about 12 mg of the naloxone hydrochloride or ahydrate thereof.

In certain embodiments, the single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient comprisesabout 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or ahydrate thereof.

In certain embodiments, the aqueous solution comprises:

-   -   between about 2 mg and about 12 mg of the naloxone hydrochloride        or a hydrate thereof;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments,

-   -   the isotonicity agent is NaCl;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In certain embodiments, the aqueous solution comprises:

-   -   about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

Also provided herein is a drug product comprising a combination of atherapeutically effective amount of an opioid agonist and atherapeutically effective amount of naloxone hydrochloride or a hydratethereof, wherein said naloxone hydrochloride or hydrate thereof iscontained in a pre-primed, bi-dose device adapted for nasal delivery ofa pharmaceutical composition to a patient, wherein a first volume ofsaid pharmaceutical composition is present in a first reservoir, and asecond volume of said pharmaceutical composition is present in a secondreservoir, and wherein said therapeutically effective amount of saidopioid antagonist is delivered essentially by a first actuation of saiddrug delivery device from said first reservoir into a nostril of saidpatient and a second actuation of said drug delivery device from saidsecond reservoir into a nostril of said patient; each reservoircomprising a pharmaceutical composition which is an aqueous solution ofabout 100 μL comprising:

-   -   an isotonicity agent;    -   benzalkonium chloride in an amount effective to function as a        permeation/penetration enhancer and/or a cationic surfactant;    -   a stabilizing agent; and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments, each reservoir of the pre-primed, bi-dose deviceadapted for nasal delivery of a pharmaceutical composition to a patientcomprises between about 2 mg and about 12 mg of the naloxonehydrochloride or a hydrate thereof.

In certain embodiments, each reservoir of the pre-primed, bi-dose deviceadapted for nasal delivery of a pharmaceutical composition to a patientcomprises about 2 mg, about 4 mg, or about 8 mg of the naloxonehydrochloride or a hydrate thereof.

In certain embodiments, the aqueous solution comprises:

-   -   between about 2 mg and about 12 mg of the naloxone hydrochloride        or a hydrate thereof;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH or 3.5-5.5.

In certain embodiments,

-   -   the isotonicity agent is NaCl;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In certain embodiments, the aqueous solution comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

In certain embodiments, each reservoir comprises about 2.2 mg of thenaloxone hydrochloride dihydrate.

In certain embodiments, each reservoir comprises about 4.4 mg of thenaloxone hydrochloride dihydrate.

Also provided herein is a method of lowering opioid overdose risk in anindividual at risk for opioid overdose, comprising providing to theindividual at risk for opioid overdose a combination of atherapeutically effective amount of an opioid agonist and atherapeutically effective amount of naloxone hydrochloride or a hydratethereof, wherein said naloxone hydrochloride or hydrate thereof iscontained in a single-use, pre-primed device adapted for nasal deliveryof a pharmaceutical composition to a patient by one actuation of saiddevice into one nostril of said patient, and wherein the single-use,pre-primed device comprises a reservoir containing a pharmaceuticalcomposition which is an aqueous solution of about 100 μL comprising:

-   -   naloxone hydrochloride or a hydrate thereof;    -   an isotonicity agent;    -   benzalkonium chloride in an amount effective to function as a        permeation/penetration enhancer and/or a cationic surfactant;    -   a stabilizing agent; and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments, the single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient comprisesbetween about 2 mg and about 12 mg of the naloxone hydrochloride or ahydrate thereof.

In certain embodiments, the single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient comprisesabout 2 mg, about 4 mg, or about 8 mg of the naloxone hydrochloride or ahydrate thereof.

In certain embodiments, the aqueous solution comprises:

-   -   between about 2 mg and about 12 mg of the naloxone hydrochloride        or a hydrate thereof;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments,

-   -   the isotonicity agent is NaCl;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In certain embodiments, the aqueous solution comprises:

-   -   about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

Also provided herein is a method of lowering opioid overdose risk in anindividual at risk for opioid overdose, comprising providing to theindividual at risk for opioid overdose a combination of atherapeutically effective amount of an opioid agonist and atherapeutically effective amount of naloxone hydrochloride or a hydratethereof, wherein said naloxone hydrochloride or hydrate thereof iscontained in a pre-primed, bi-dose device adapted for nasal delivery ofa pharmaceutical composition to a patient, wherein a first volume ofsaid pharmaceutical composition is present in a first reservoir, and asecond volume of said pharmaceutical composition is present in a secondreservoir, and wherein said therapeutically effective amount of saidopioid antagonist is delivered essentially by a first actuation of saiddrug delivery device from said first reservoir into a nostril of saidpatient and a second actuation of said drug delivery device from saidsecond reservoir into a nostril of said patient; each reservoircomprising a pharmaceutical composition which is an aqueous solution ofabout 100 μL comprising:

-   -   naloxone hydrochloride or a hydrate thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   benzalkonium chloride in an amount effective to function as a        permeation/penetration enhancer and/or a cationic surfactant;    -   a stabilizing agent; and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments, the single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient comprisesbetween about 2 mg and about 12 mg of the naloxone hydrochloride or ahydrate thereof.

In certain embodiments, each reservoir of the single-use, pre-primeddevice adapted for nasal delivery of a pharmaceutical composition to apatient comprises about 2 mg, about 4 mg, or about 8 mg of the naloxonehydrochloride or a hydrate thereof.

In certain embodiments, each reservoir comprises about 2 mg of thenaloxone hydrochloride or a hydrate thereof.

In certain embodiments, each reservoir comprises about 4 mg of thenaloxone hydrochloride or a hydrate thereof.

In certain embodiments, the aqueous solution comprises:

-   -   between about 2 mg and about 12 mg of the naloxone hydrochloride        or a hydrate thereof;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In certain embodiments,

-   -   the isotonicity agent is NaCl;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In certain embodiments, each reservoir comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   between about 0.001 mg and about 0.1 mg (i.e., about 0.01% w/v        to about 1% w/v) benzalkonium chloride; and    -   about 0.2 mg disodium edetate.

In some embodiments, said pharmaceutical composition further comprisesone or more excipients selected from water, NaCl, benzalkonium chloride,sodium edetate, disodium edetate, and hydrochloric acid.

In some embodiments, said pharmaceutical composition further compriseswater, NaCl, benzalkonium chloride, disodium edetate, and hydrochloricacid.

In some embodiments, said pharmaceutical composition further comprises:

-   -   an isotonicity agent;    -   a preservative;    -   a stabilizing agent;    -   an amount of acid sufficient to achieve a pH of 3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments, said pharmaceutical composition comprises:

-   -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH of 3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative, cationic surfactant,        and/or permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, said pharmaceutical composition comprises:

-   -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate;    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5; and    -   an amount of water sufficient to achieve a final volume of about        100 μL.

In some embodiments, said device is filled with said pharmaceuticalcomposition using sterile filling.

In some embodiments, said pharmaceutical composition is storage-stablefor about twelve months at about 25° C. and about 60% relative humidity.

In some embodiments, said device is a single-dose device, wherein saidpharmaceutical composition is present in one reservoir, and wherein saidtherapeutically effective amount of said opioid antagonist is deliveredessentially by one actuation of said device into one nostril of saidpatient.

In some embodiments, about 100 μL of said pharmaceutical composition isdelivered by said actuation.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of less than 20 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at t_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy att_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at t_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 2 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 4 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 6 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist.

In some embodiments, said device is a bi-dose device, wherein a firstvolume of said pharmaceutical composition is present in a firstreservoir and a second volume of said pharmaceutical composition ispresent in a second reservoir, and wherein said therapeuticallyeffective amount is delivered essentially by a first actuation of saiddevice into a first nostril of said patient and a second actuation ofsaid device into a second nostril of said patient.

In some embodiments, said first volume and said second volume combinedis equal to not more than about 380 μL.

In some embodiments, about 100 μL of said first volume of saidpharmaceutical composition is delivered by said first actuation.

In some embodiments, about 100 μL of said second volume of saidpharmaceutical composition is delivered by said second actuation.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at t_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy att_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at t_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 2 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 4 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 6 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist.

Also provided herein is a single-use, pre-primed device adapted fornasal delivery of a pharmaceutical composition to a patient by oneactuation of said device into one nostril of said patient, having asingle reservoir comprising about 100 μL of a pharmaceutical compositionwhich is an aqueous solution comprising:

-   -   about 2 mg or about 4 mg naloxone hydrochloride or a hydrate        thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In some embodiments, the device comprises about 4 mg naloxonehydrochloride or a hydrate thereof. In some embodiments, the devicecomprises about 2 mg naloxone hydrochloride or a hydrate thereof. Insome embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative cationic surfactant and/or        permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, the device comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

In some embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidnaloxone hydrochloride in said patient has a t_(max) of between about 20and about 30 minutes.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 30 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of about 18.5 minutes.

In some embodiments, delivery of said therapeutically effective amountto said patient, provides occupancy at t_(max) of said opioid antagonistat the opioid receptors in the respiratory control center of saidpatient of greater than about 90%. In some embodiments, delivery of saidtherapeutically effective amount to said patient, provides occupancy att_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said therapeutically effective amount tosaid patient, provides occupancy at t_(max) of said opioid antagonist atthe opioid receptors in the respiratory control center of said patientof greater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 2 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 4 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 6 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist.

In some embodiments, said device is filled with said pharmaceuticalcomposition using sterile filling.

In some embodiments, said pharmaceutical composition is storage-stablefor about twelve, about fifteen, or even about eighteen months at about25° C. and about 60% relative humidity.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

Also provided are devices as recited in any of the preceding embodimentsfor use in the treatment of an opioid overdose symptom selected from:respiratory depression, postoperative opioid respiratory depression,altered level consciousness, miotic pupils, cardiovascular depression,hypoxemia, acute lung injury, aspiration pneumonia, sedation, andhypotension.

Also provided are devices as recited in any of the preceding embodimentsfor use in the reversal of respiratory depression induced by opioids.

In some embodiments, said respiratory depression is caused by theillicit use of opioids or by an accidental misuse of opioids duringmedical opioid therapy.

Also provided are devices as recited in any of the preceding embodimentsfor use in the complete or partial reversal of narcotic depression,including respiratory depression, induced by opioids selected from:natural and synthetic narcotics, propoxyphene, methadone, nalbuphine,pentazocine and butorphanol.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual.

Also provided are kits comprising a device described herein and writteninstructions for using the device. Also provided are kits comprising adevice described herein and an opioid agonist. In some embodiments thekit further comprises written instructions. In some embodiments, theopioid agonist is selected from codeine, morphine, methadone, fentanyl,oxycodone HCl, hydrocodone bitartrate, hydromorphone, oxymorphone,meperidine, propoxyphene, opium, heroin, and certain narcotic-antagonistanalgesics, such as, nalbuphine, pentazocine and butorphanol. In someembodiments, the opioid agonist is selected from tapentadol andtramadol.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

Tamper-proof and tamper-resistant formulating technologies have beendeveloped for safer delivery of opioid antagonists, but suchformulations are still abused resulting in opioid overdose. One suchtechnology (Abuse Deterrent Prolonged Release Erosion Matrix (ADPREM);Egalet) utilizes a water-degradable polymer matrix technology thaterodes from the surface at a constant rate. The matrix consists of oneor more plasticizing polymers that cannot be crushed or melted. Anothersuch technology (Abuse Resistant Technology (ART); Elite Laboratories)utilizes a proprietary coating technology consisting of various polymersthat can sequester an opioid antagonist (naltrexone) in fragilemicropellets that are indistinguishable from the pellets containing theopioid. The formulation is designed to release sequestered antagonistonly if the dosage is crushed or otherwise damaged for extraction. Oraldosage forms are prepared by coating powders, crystals, granules, orpellets with various polymers to impart different characteristics. Theformulations can release the active drug in both immediate and sustainedrelease form. Chronodelivery formulations using this technology caneffectively delay drug absorption for up to five hours. Aversion (AcuraPharmaceuticals) utilizes certain proprietary combinations of functionalexcipients (e.g., gelling agents) and active ingredients intended todiscourage the most common methods of prescription drug misuse andabuse. Ingredients may include nasal irritants (e.g., capsaicin) andaversive agents (e.g., niacin). In some embodiments, the opioid agonistis in a tamper-proof formulation. In some embodiments, the opioidagonist is in a tamper-resistant formulation. In some embodiments, theopioid agonist is selected from Acurox® Oxycodone DETERx®, Oxycontin®,Egalet hydrocodone, Egalet morphine, Egalet oxycodone, Exalgo®, Opana®,Opana® ER, Vicodin®, Percocet® and Remoxy®.

Pharmaceutical Compositions

Also provided are pharmaceutical compositions comprising one or moreopioid antagonist. In some embodiments the pharmaceutical compositionscomprise an opioid antagonist and a pharmaceutically acceptable carrier.The carrier(s) must be “acceptable” in the sense of being compatiblewith the other ingredients of the formulation and not overly deleteriousto the recipient thereof. Some embodiments of the present inventioninclude a method of producing a pharmaceutical composition comprisingadmixing at least one opioid antagonist and a pharmaceuticallyacceptable carrier. Pharmaceutical compositions are applied directly tothe nasal cavity using the devices described herein. In the case of aspray, this may be achieved for example by means of a metering atomizingspray pump.

Liquid preparations include solutions, suspensions and emulsions, forexample, water or water-propylene glycol solutions. Additionalingredients in liquid preparations may include: antimicrobialpreservatives, such as benzalkonium chloride (which may also act as acationic surfactant and/or a permeation enhancer), methylparaben, sodiumbenzoate, benzoic acid, phenyl ethyl alcohol, and the like, and mixturesthereof; surfactants such as Polysorbate 80 NF, polyoxyethylene 20sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate,polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitanmonostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene20 sorbitan tristearate, polyoxyethylene (5) sorbitan monooleate,polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 20 sorbitanmonoisostearate, sorbitan monooleate, sorbitan monolaurate, sorbitanmonopalmitate, sorbitan monostearate, sorbitan trilaurate, sorbitantrioleate, sorbitan tristearate, polyethylene glycol(15)-hydroxystearate (Solutol® HS 15) and the like, and mixturesthereof; a tonicity agent such as: dextrose, lactose, sodium chloride,calcium chloride, magnesium chloride, sorbitol, sucrose, mannitol,trehalose, raffinose, polyethylene glycol, hydroxyethyl starch, glycine,and the like, and mixtures thereof; and a suspending agent such asmicrocrystalline cellulose, carboxymethylcellulose sodium NF,polyacrylic acid, magnesium aluminum silicate, xanthan gum, and thelike, and mixtures thereof.

The opioid antagonists described herein can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington: TheScience and Practice of Pharmacy, 21st ed., Lippincott Williams &Wilkins, Philadelphia, Pa. (2005).

The opioid antagonists described herein may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, oxalic, μ-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed by Berge et al., Journal ofPharmaceutical Sciences, 66:1-19 (1977). The acid addition salts may beobtained as the direct products of compound synthesis. In thealternative, the free base may be dissolved in a suitable solventcontaining the appropriate acid and the salt isolated by evaporating thesolvent or otherwise separating the salt and solvent. The opioidantagonists described herein may form solvates with standard lowmolecular weight solvents using methods known to the skilled artisan.

Accordingly, provided herein are pharmaceutical formulations forintranasal administration comprising, in an aqueous solution of not morethan about 140 μL:

-   -   between about 2 mg and about 12 mg of an opioid antagonist;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of an acid sufficient to achieve a pH of 3.5-5.5.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride,or a hydrate thereof.

In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, the pharmaceutical formulation comprises an amountequivalent to about 4 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the pharmaceutical formulation comprises an amountequivalent to an amount chosen from about 2 mg naloxone hydrochloride,about 4 mg of naloxone hydrochloride, and about 8 mg naloxonehydrochloride. In some embodiments, the pharmaceutical formulationcomprises an amount equivalent to about 2 mg of naloxone hydrochloride.In some embodiments, the pharmaceutical formulation comprises an amountequivalent to about 4 mg of naloxone hydrochloride. In some embodiments,the pharmaceutical formulation comprises an amount equivalent to about 8mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 3.4 mg of naloxonehydrochloride.

In some embodiments, the pharmaceutical formulation comprises about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, the pharmaceutical formulation comprises about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,the pharmaceutical formulation comprises an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, the pharmaceutical formulation comprisesabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,the pharmaceutical formulation comprises about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, the pharmaceuticalformulation comprises about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, the device comprises about 4.4 mg naloxonehydrochloride dihydrate. In some embodiments, the device comprises about2.2 mg naloxone hydrochloride dihydrate.

In some embodiments, the pharmaceutical composition is in an aqueoussolution of about 100 μL.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidnaloxone hydrochloride in said patient has a t_(max) of between about 20and about 30 minutes.

In some embodiments, said device is actuatable with one hand.

In some embodiments, the delivery time is less than about 25 seconds. Insome embodiments, the delivery time is less than about 20 seconds.

In some embodiments, the 90% confidence interval for dose delivered peractuation is ±about 2%. In some embodiments, the 95% confidence intervalfor dose delivered per actuation is ±about 2.5%.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally. In some embodiments, upon nasal delivery of saidpharmaceutical composition to said patient, less than about 10% of saidpharmaceutical composition leaves the nasal cavity via drainage into thenasopharynx or externally. In some embodiments, upon nasal delivery ofsaid pharmaceutical composition to said patient, less than about 5% ofsaid pharmaceutical composition leaves the nasal cavity via drainageinto the nasopharynx or externally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in a patient has a t_(max) of less than 30 minutes. Insome embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 25 minutes.In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of about 20 minutes. Insome embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of less than 19 minutes.In some embodiments, the plasma concentration versus time curve of theopioid antagonist in the patient has a t_(max) of about 18.5 minutes.

In some embodiments, delivery of said pharmaceutical formulation to apatient, provides occupancy at t_(max) of said opioid antagonist at theopioid receptors in the respiratory control center of said patient ofgreater than about 90%. In some embodiments, delivery of saidpharmaceutical formulation to said patient, provides occupancy att_(max) of said opioid antagonist at the opioid receptors in therespiratory control center of said patient of greater than about 95%. Insome embodiments, delivery of said pharmaceutical formulation to saidpatient, provides occupancy at t_(max) of said opioid antagonist at theopioid receptors in the respiratory control center of said patient ofgreater than about 99%.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 2 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 4 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist. In someembodiments, said patient is free from respiratory depression for atleast about 6 hours following treatment comprising delivery of saidtherapeutically effective amount of said opioid antagonist.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of not more than about140 μL:

-   -   about 2 mg or about 4 mg naloxone hydrochloride or a hydrate        thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In some embodiments,

-   -   the isotonicity agent is NaCl;    -   the compound which is a preservative, cationic surfactant,        and/or permeation enhancer is benzalkonium chloride;    -   the stabilizing agent is disodium edetate; and    -   the acid is hydrochloric acid.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 2.2 mg or about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises about 4 mgnaloxone hydrochloride or a hydrate thereof. In some embodiments, thepharmaceutical formulation comprises about 2 mg naloxone hydrochlorideor a hydrate thereof. In some embodiments, the pharmaceuticalformulation comprises about 4.4 mg naloxone hydrochloride dihydrate. Insome embodiments, the pharmaceutical formulation comprises about 2.2 mgnaloxone hydrochloride dihydrate.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of about 100 μL:

-   -   about 4 mg naloxone hydrochloride or a hydrate thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of acid sufficient to achieve a pH of 3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 4.4 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.01 mg benzalkonium chloride;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

Also provided herein are pharmaceutical formulations for intranasaladministration comprising, in an aqueous solution of about 100 μL:

-   -   about 2 mg naloxone hydrochloride or a hydrate thereof;    -   between about 0.2 mg and about 1.2 mg of an isotonicity agent;    -   between about 0.005 mg and about 0.015 mg of a compound which is        a preservative, cationic surfactant, and/or permeation enhancer;    -   between about 0.1 mg and about 0.5 mg of a stabilizing agent;        and    -   an amount of an acid sufficient to achieve a pH of 3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises:

-   -   about 2.2 mg naloxone hydrochloride dihydrate;    -   about 0.74 mg NaCl;    -   about 0.2 mg disodium edetate; and    -   an amount of hydrochloric acid sufficient to achieve a pH of        3.5-5.5.

In some embodiments, the pharmaceutical formulation comprises about 4.4mg naloxone hydrochloride dihydrate. In some embodiments, thepharmaceutical formulation comprises about 2.2 mg naloxone hydrochloridedihydrate.

Provided are devices adapted for nasal delivery of a pharmaceuticalcomposition to a patient, comprising a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the device is pre-primed, and whereinthe therapeutically effective amount, is equivalent to about 2 mg toabout 12 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride. In some embodiments, the pharmaceuticalcomposition comprises a solution of naloxone hydrochloride dihydrate. Insome embodiments, the pharmaceutical composition further comprises oneor more excipients selected from water and NaCl. In some embodiments,the pharmaceutical composition is substantially free of antimicrobialpreservatives. In some embodiments, the device is substantially free ofbenzalkonium chloride, methylparaben, sodium benzoate, benzoic acid,phenyl ethyl alcohol. In some embodiments, the device is filled with thepharmaceutical composition in a sterile environment. In someembodiments, the pharmaceutical composition is storage-stable for abouttwelve months at about 25° C. In some embodiments, the pharmaceuticalcomposition comprises less than 0.1% w/w antimicrobial preservatives. Insome embodiments, the pharmaceutical composition comprises 0.01% w/w orless antimicrobial preservatives. In some embodiments, thepharmaceutical composition comprises 0.01% w/w-0.001% w/w antimicrobialpreservatives. In some embodiments, the pharmaceutical compositioncomprises less than 0.001% w/w antimicrobial preservatives.

Also provided are devices for “combination-therapy” comprisingpharmaceutical compositions comprising at least one opioid antagonistdescribed herein, together with at least one known pharmaceutical agentand a pharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition comprises a short-acting opioid antagonistand a long-acting opioid antagonist. In some embodiments, thepharmaceutical composition comprises naloxone and naltrexone. In someembodiments, the pharmaceutical composition comprises naloxone andmethylnaltrexone. In some embodiments, the pharmaceutical compositioncomprises naloxone and nalmefene.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

Indications

Also provided are devices for use in treating opioid overdose andsymptoms thereof and methods of using the devices. Naloxone prevents orreverses the effects of opioids including respiratory depression,sedation and hypotension. Also, it can reverse the psychotomimetic anddysphoric effects of agonist-antagonists such as pentazocine. Naloxonecauses abrupt reversal of narcotic depression which may result innausea, vomiting, sweating, tachycardia, increased blood pressure,tremulousness, seizures and cardiac arrest, however, there is noclinical experience with naloxone hydrochloride overdosage in humans.For this reason, also described herein is a method of preventingcomplications from severe opioid withdrawal, the method comprisingadministering a dose of naloxone according to the devices and/orformulations disclosed herein, and then monitoring the patient for asymptom selected from the group consisting of vomiting, sweating,tachycardia, increased blood pressure, tremulousness, seizures andcardiac arrest. In the mouse and rat the intravenous LD50 is 150±5 mg/kgand 109±4 mg/kg respectively. In acute subcutaneous toxicity studies innewborn rats the LD50 (95% CL) is 260 (228-296) mg/kg. Subcutaneousinjection of 100 mg/kg/day in rats for 3 weeks produced only transientsalivation and partial ptosis following injection: no toxic effects wereseen at 10 mg/kg/day for 3 weeks.

Naloxone hydrochloride injection is indicated for the complete orpartial reversal of narcotic depression, including respiratorydepression, induced by opioids selected from: natural and syntheticnarcotics, propoxyphene, methadone, and certain narcotic-antagonistanalgesics: nalbuphine, pentazocine and butorphanol. Naloxonehydrochloride is also indicated for the diagnosis of suspected acuteopioid overdosage. For the treatment of known or suspected narcoticoverdose in adults an initial dose of 0.4 mg to 2 mg of naloxonehydrochloride intravenously is indicated. If the desired degree ofcounteraction and improvement in respiratory functions is not obtained,administration may be repeated at 2 to 3 minute intervals. If noresponse is observed after 10 mg of naloxone hydrochloride have beenadministered, the diagnosis of narcotic-induced or partialnarcotic-induced toxicity should be questioned. The usual initial dosein children is 0.01 mg/kg body weight given IV. If this dose does notresult in the desired degree of clinical improvement, a subsequent doseof 0.1 mg/kg body weight may be administered. When using naloxonehydrochloride injection in neonates a product containing 0.02 mg/mL(i.e., 0.002% w/v) should be used.

It has also been reported that naloxone hydrochloride is an effectiveagent for the reversal of the cardiovascular and respiratory depressionassociated with narcotic and possibly some non-narcotic overdoses. Theauthors stated that due to naloxone's pharmacokinetic profile, acontinuous infusion protocol is recommended when prolonged narcoticantagonist effects are required. (Handal et al., Ann Emerg Med. 1983July; 12(7):438-45).

Accordingly, also provided herein are methods of treating opioidoverdose or a symptom thereof, comprising nasally administering to apatient in need thereof a therapeutically effective amount of an opioidantagonist selected from naloxone and pharmaceutically acceptable saltsthereof, wherein said therapeutically effective amount is equivalent toabout 2 mg to about 12 mg of naloxone hydrochloride or a hydratethereof. In some embodiments, the therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof is delivered in not more than about 140 μL of an aqueouscarrier solution.

In certain embodiments, also provided herein are methods of treatingopioid overdose or a symptom thereof, comprising nasally administeringto a patient in need thereof a therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof, wherein said therapeutically effective amount isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride or ahydrate thereof in not more than about 140 μL of an aqueous carriersolution.

In certain embodiments are provided methods of treating opioid overdose,or a symptom thereof, comprising nasally administering with a spraydevice to a patient in need thereof a therapeutically effective amountof an opioid antagonist selected from naloxone and pharmaceuticallyacceptable salts thereof, wherein the spray device is capable ofspraying droplets having a median droplet size between about 30 andabout 100 μm.

In some embodiments, the spray device is capable of spraying aformulation having a median distribution volume (Dv(50)) Dv(50) of 30-70μm and a Dv(90)<100 μm.

In certain embodiments, the spray device is capable of spraying in amanner that the percent of droplets less than 10 μm is less than 10%. Incertain embodiments, the percent of droplets less than 10 μm is lessthan 5%. In certain embodiments, the percent of droplets less than 10 μmis less than 2%. In certain embodiments, the percent of droplets lessthan 10 μm is less than 1%.

In certain embodiments, the spray device is capable of spraying auniform circular plume spray pattern with an ovality ratio close to 1.Ovality ratio is calculated as the quotient of the maximum diameter(Dmax) and the minimum diameter (Dmin) of a spray pattern takenorthogonal to the direction of spray flow (e.g., from the “top”). Incertain embodiments, the ovality ratio is less than 2.0. In certainembodiments, the ovality ratio is less than 1.5. In certain embodiments,the ovality ratio is less than 1.3. In certain embodiments, the ovalityratio is less than 1.2. In certain embodiments, the ovality ratio isless than 1.1. In certain embodiments, the ovality ratio is about 1.0.

In certain embodiments, also provided herein are methods of treatingopioid overdose or a symptom thereof, comprising nasally administeringto a patient in need thereof a single dose of a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein said therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride or a hydrate thereof in not more than about 140 μL of anaqueous carrier solution.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride.In some embodiments, said opioid antagonist is naloxone hydrochloridedihydrate.

In some embodiments, said pharmaceutical composition comprises asolution of naloxone hydrochloride, or a hydrate thereof.

In some embodiments, said patient is an opioid overdose patient or asuspected opioid overdose patient.

In some embodiments, said patient is in a lying, supine, or recoveryposition. In some embodiments, said patient is in a lying position. Insome embodiments, said patient is in a supine position. In someembodiments, said patient is in a recovery position.

In some embodiments, said therapeutically effective amount of an opioidantagonist is delivered by an untrained individual.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg to about 10 mg of naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent to anamount chosen from about 2 mg naloxone hydrochloride, about 4 mg ofnaloxone hydrochloride, and about 8 mg naloxone hydrochloride. In someembodiments, said therapeutically effective amount is equivalent toabout 2 mg of naloxone hydrochloride. In some embodiments, saidtherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, said therapeutically effectiveamount is equivalent to about 8 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3.4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is about 2.2mg to about 13.2 mg of naloxone hydrochloride dihydrate. In someembodiments, said therapeutically effective amount is about 4.4 mg toabout 11 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is an amount chosen from about 2.2mg naloxone hydrochloride dihydrate, about 4.4 mg of naloxonehydrochloride dihydrate, and about 8.8 mg naloxone hydrochloridedihydrate. In some embodiments, said therapeutically effective amount isabout 2.2 mg of naloxone hydrochloride dihydrate. In some embodiments,said therapeutically effective amount is about 4.4 mg of naloxonehydrochloride dihydrate. In some embodiments, said therapeuticallyeffective amount is about 8.8 mg of naloxone hydrochloride dihydrate.

In some embodiments, said symptom is chosen from respiratory depressionand central nervous system depression.

In some embodiments, said patient exhibits any of unresponsiveness tostimulus, unconsciousness, stopped breathing; erratic or stopped pulse,choking or gurgling sounds, blue or purple fingernails or lips, slack orlimp muscle tone, contracted pupils, and vomiting.

In some embodiments, said patient is not breathing.

In some embodiments, said patient is in a lying, supine, or recoveryposition.

In some embodiments, said patient is in a lying position.

In some embodiments, said patient is in a supine position.

In some embodiments, said patient is a recovery position.

In some embodiments, said therapeutically effective amount is equivalentto about 2 mg to about 10 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto an amount chosen from about 2 mg naloxone hydrochloride, about 4 mgof naloxone hydrochloride, and about 8 mg naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 2 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 4 mg of naloxone hydrochloride.

In some embodiments, said therapeutically effective amount is equivalentto about 8 mg of naloxone hydrochloride.

In some embodiments, said opioid antagonist is the only pharmaceuticallyactive compound in said pharmaceutical composition.

In some embodiments, said opioid antagonist is naloxone hydrochloride.

In some embodiments, said nasally administering is accomplished using apre-primed device adapted for nasal delivery of a pharmaceuticalcomposition.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 20% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 10% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, upon nasal delivery of said pharmaceuticalcomposition to said patient, less than about 5% of said pharmaceuticalcomposition leaves the nasal cavity via drainage into the nasopharynx orexternally.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 30 minutes.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of less than 25 minutes.

In some embodiments, the plasma concentration versus time curve of saidopioid antagonist in said patient has a t_(max) of about 20 minutes.

In some embodiments, said opioid overdose symptom is selected from:respiratory depression, central nervous system depression, andcardiovascular depression.

In some embodiments, said opioid overdose symptom is respiratorydepression induced by opioids.

In some embodiments, said respiratory depression is caused by theillicit use of opioids or by an accidental misuse of opioids duringmedical opioid therapy.

In some embodiments, said respiratory depression is induced by opioidsselected from: natural and synthetic narcotics, propoxyphene, methadone,nalbuphine, pentazocine and butorphanol.

In some embodiments, said respiratory depression is induced by an opioidselected from codeine, morphine, methadone, fentanyl, oxycodone HCl,hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine,propoxyphene, opium, heroin, tramadol, tapentadol.

In some embodiments, said patient is free from respiratory depressionfor at least about 1 hour following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 2 hours following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 4 hours following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist.

In some embodiments, said patient is free from respiratory depressionfor at least about 6 hours following treatment comprising delivery ofsaid therapeutically effective amount of said opioid antagonist.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

Also provided are the devices, pharmaceutical compositions, kits, andmethods of treatment described herein for use in the treatment of anopioid overdose symptom selected from: respiratory depression,postoperative opioid respiratory depression, altered levelconsciousness, miotic pupils, cardiovascular depression, hypoxemia,acute lung injury, aspiration pneumonia, sedation, and hypotension. Alsoprovided are the devices, pharmaceutical compositions, kits, and methodsof treatment described herein for use in the reversal of respiratorydepression induced by opioids. In some embodiments, the respiratorydepression is caused by the illicit use of opioids or by an accidentalmisuse of opioids during medical opioid therapy. Also provided are thedevices, pharmaceutical compositions, kits, and methods of treatmentdescribed herein for use in the complete or partial reversal of narcoticdepression, including respiratory depression, induced by opioidsselected from: natural and synthetic narcotics, propoxyphene, methadone,nalbuphine, pentazocine and butorphanol. In some embodiments, narcoticdepression, including respiratory depression, is induced by an opioidagonist selected from codeine, morphine, methadone, fentanyl, oxycodoneHCl, hydrocodone bitartrate, hydromorphone, oxymorphone, meperidine,propoxyphene, opium, heroin, tramadol, and tapentadol.

Also provided are devices, pharmaceutical formulations, and kits for,and methods of, treating opioid overdose or a symptom thereof,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist selected fromnaloxone and pharmaceutically acceptable salts thereof, wherein thetherapeutically effective amount is equivalent to about 2 mg to about 12mg of naloxone hydrochloride. In some embodiments, the patient is notbreathing. Also provided are devices adapted for nasal delivery of apharmaceutical composition to a patient, comprising a therapeuticallyeffective amount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the device ispre-primed, and wherein the therapeutically effective amount, isequivalent to about 4 mg to about 12 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 2 mg to about 24 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about3 mg to about 18 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg to about 10mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 5 mg to about 11 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 6 mg to about 10 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg to about 8 mg of naloxone hydrochloride. In some embodiments,the therapeutically effective amount is equivalent to about 7 mg toabout 9 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 3.4 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 5 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 6 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 7 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about8 mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 9 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 10 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 11 mg ofnaloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 12 mg of naloxone hydrochloride.In some embodiments, the opioid antagonist is the only pharmaceuticallyactive compound in pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, theopioid antagonist is anhydrous naloxone hydrochloride. In someembodiments, the opioid antagonist is the only pharmaceutically activecompound in said pharmaceutical composition. In some embodiments, theopioid antagonist is naloxone hydrochloride. In some embodiments, thepharmaceutical composition comprises a solution of naloxonehydrochloride. In some embodiments, the nasally administering isaccomplished using a device described herein. In some embodiments, theopioid overdose symptom is selected from: respiratory depression,postoperative opioid respiratory depression, altered levelconsciousness, miotic pupils, cardiovascular depression, hypoxemia,acute lung injury, aspiration pneumonia, sedation, and hypotension. Insome embodiments, the opioid overdose symptom is respiratory depressioninduced by opioids. In some embodiments, the respiratory depression iscaused by the illicit use of opioids or by an accidental misuse ofopioids during medical opioid therapy. In some embodiments, therespiratory depression is induced by opioids selected from: natural andsynthetic narcotics, propoxyphene, methadone, nalbuphine, pentazocineand butorphanol. In some embodiments, the respiratory depression isinduced by an opioid agonist selected from codeine, morphine, methadone,fentanyl, oxycodone HCl, hydrocodone bitartrate, hydromorphone,oxymorphone, meperidine, propoxyphene, opium, heroin, tramadol, andtapentadol.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid overdose or a symptom thereof,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist together and atleast one known pharmaceutical agent. In some embodiments, the methodcomprises nasally administering to a patient in need thereoftherapeutically effective amounts of a short-acting opioid antagonistand a long-acting opioid antagonist. In some embodiments, the methodcomprises nasally administering to a patient in need thereoftherapeutically effective amounts of naloxone and naltrexone. In someembodiments, the method comprises nasally administering to a patient inneed thereof therapeutically effective amounts of naloxone andmethylnaltrexone. In some embodiments, the method comprises nasallyadministering to a patient in need thereof therapeutically effectiveamounts of naloxone and nalmefene.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, reversing the psychotomimetic and dysphoric effects ofagonist-antagonists such as pentazocine, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 4.4 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about4 mg of naloxone hydrochloride dihydrate. In some embodiments, thenasally administering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, diagnosis of suspected acute opioid overdosage,comprising nasally administering to a patient in need thereof atherapeutically effective amount of an opioid antagonist selected fromnaloxone and pharmaceutically acceptable salts thereof, wherein thetherapeutically effective amount is equivalent to about 2 mg to about 12mg of naloxone hydrochloride. In some embodiments, the therapeuticallyeffective amount is equivalent to about 4 mg of naloxone hydrochloride.In some embodiments, the therapeutically effective amount is equivalentto about 4.4 mg of naloxone hydrochloride dihydrate. In someembodiments, the nasally administering is accomplished using a devicedescribed herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid addiction, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist selected from naloxone andpharmaceutically acceptable salts thereof, wherein the therapeuticallyeffective amount is equivalent to about 2 mg to about 12 mg of naloxonehydrochloride. In some embodiments, the therapeutically effective amountis equivalent to about 4 mg of naloxone hydrochloride. In someembodiments, the therapeutically effective amount is equivalent to about4.4 mg of naloxone hydrochloride dihydrate. In some embodiments, thenasally administering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating septic shock, comprising nasally administeringto a patient in need thereof a therapeutically effective amount of anopioid antagonist selected from naloxone and pharmaceutically acceptablesalts thereof, wherein the therapeutically effective amount isequivalent to about 2 mg to about 12 mg of naloxone hydrochloride. Insome embodiments, the therapeutically effective amount is equivalent toabout 4 mg of naloxone hydrochloride. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride dihydrate. In some embodiments, the nasallyadministering is accomplished using a device described herein.

Also provided are devices, kits, and pharmaceutical formulations for,and methods of, treating opioid overdose or a symptom thereof, reversingthe psychotomimetic and dysphoric effects of agonist-antagonists such aspentazocine, diagnosing suspected acute opioid overdosage, treatingopioid addiction, or treating septic shock, comprising nasallyadministering to a patient in need thereof a therapeutically effectiveamount of an opioid antagonist, wherein the therapeutically effectiveamount is about 2 mg to about 12 mg. In some embodiments, thetherapeutically effective amount is equivalent to about 4.4 mg ofnaloxone hydrochloride dihydrate. In some embodiments, thetherapeutically effective amount is equivalent to about 4 mg of naloxonehydrochloride. In some embodiments, the patient is an opioid overdosepatient. In some embodiments, the patient is not breathing. In someembodiments, the opioid antagonist is the only pharmaceutically activecompound in said pharmaceutical composition. In some embodiments, theopioid antagonist is selected from naltrexone, methylnaltrexone, andnalmefene, and pharmaceutically acceptable salts thereof. In someembodiments, the opioid antagonist is naltrexone hydrochloride. In someembodiments, the opioid antagonist is methylnaltrexone bromide. In someembodiments, the opioid antagonist is nalmefene hydrochloride. In someembodiments, the nasally administering is accomplished using a devicedescribed herein. In some embodiments, the opioid overdose symptom isselected from: respiratory depression, postoperative opioid respiratorydepression, altered level consciousness, miotic pupils, cardiovasculardepression, hypoxemia, acute lung injury, aspiration pneumonia,sedation, and hypotension. In some embodiments, the opioid overdosesymptom is respiratory depression induced by opioids. In someembodiments, the respiratory depression is caused by the illicit use ofopioids or by an accidental misuse of opioids during medical opioidtherapy. In some embodiments, the respiratory depression is induced byopioids selected from: natural and synthetic narcotics, propoxyphene,methadone, nalbuphine, pentazocine and butorphanol. In some embodiments,the respiratory depression is induced by an opioid agonist selected fromcodeine, morphine, methadone, fentanyl, oxycodone HCl, hydrocodonebitartrate, hydromorphone, oxymorphone, meperidine, propoxyphene, opium,heroin, tramadol, and tapentadol.

Also provided are embodiments wherein any embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive. Also provided herein are uses inthe treatment of indications or one or more symptoms thereof asdisclosed herein, and uses in the manufacture of medicaments for thetreatment of indications or one or more symptoms thereof as disclosedherein, equivalent in scope to any embodiment disclosed herein, or anycombination thereof that is not mutually exclusive. The methods and usesmay employ any of the devices disclosed herein or any combinationthereof that is not mutually exclusive, or any of the pharmaceuticalformulations disclosed herein or any combination thereof that is notmutually exclusive.

Receptor Occupancy

Also provided are devices for use in treating opioid overdose andsymptoms thereof and methods of using the devices, which provide a highlevel of brain opioid receptor occupancy as may be determined, forexample, by positron emission tomography (PET). PET and single-photonemission computed tomography (SPECT) are noninvasive imaging techniquesthat can give insight into the relationship between target occupancy anddrug efficacy, provided a suitable radioligand is available. AlthoughSPECT has certain advantages (e.g., a long half-life of theradionuclides), the spatial and temporal resolution as well as thelabeling possibilities of this technique are limited.

PET involves the administration to a subject of a positron-emittingradionuclide tracer followed by detection of the positron emission(annihilation) events in the body. The radionuclide tracer is typicallycomposed of a targeting molecule having incorporated therein one or moretypes of positron-emitting radionuclides. Positron-emittingradionuclides include ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁵²Fe, ⁶²Cu, ⁶⁴Cu, ⁶⁸Ga, ⁷⁴As,⁸²Rb, ⁸⁹Zr, ¹²²I and ¹²⁴I. Non-metal radionuclides may be covalentlylinked to the targeting molecule by reactions well known from the stateof art. When the radionuclide is a metallic positron-emitter, it isunderstood that labeling may require the use of a chelating agent. Suchchelating agents are well known from the state of the art.

The positron-emitter labeled compound is administered directly, e.g.,IV, or indirectly, e.g., IN, into the subject's vascular system, fromwhere it passes through the blood-brain barrier. Once the tracer has hadsufficient time to associate with the target of interest, the individualis placed within in a scanning device comprising ring of scintillationdetectors. An emitted positron travels through the individual's tissuefor a short (isotope-dependent) distance, until it interacts with anelectron. The interaction annihilates both the electron and thepositron, producing a pair of photons moving in approximately oppositedirections. These are detected when they reach a scintillator in thescanning device. Photons that do not arrive in pairs are ignored. Animage is then generated of the part of the individual's brain to whichthe compound has distributed.

PET studies are useful for comparing nasal delivery of naloxone usingthe devices and at the doses described herein, to typical nasal doses ofnaloxone (such as 1-2 mg), to delivery of naloxone using other nasaldevices (such as the MAD™) and by other routes of administration such IMor IV naloxone or oral naltrexone or nalmefene. Further comparisons maybe made between nasal administration in the upright versus the lying orsupine positions. Useful measures that may be determined in such studiesare the time to onset of action, brain half-life, and the percentreceptor binding or occupancy of a patient's opioid receptors, forexample, the μ-opioid receptors in the respiratory center in the medullaoblongata.

[¹¹C]Carfentanil (CFN) is a μ-opioid agonist used for in vivo PETstudies of p-opioid receptors. One such study involved healthy malevolunteers assigned at enrolment to receive either naltrexone or a novelμ-opioid receptor inverse agonist (GSK1521498) (Rabiner et al.,Pharmacological differentiation of opioid receptor antagonists bymolecular and functional imaging of target occupancy and foodreward-related brain activation in humans. Molecular Psychiatry (2011)16, 826-835). Each participant underwent up to three [¹¹C]-carfentanilPET scans and two functional magnetic resonance imaging (fMRI)examinations: one [¹¹C]-carfentanil PET scan and one fMRI scan atbaseline (before dosing) and up to two PET scans and one fMRI scanfollowing oral administration of a single dose of GSK1521498 ornaltrexone. The administered doses of GSK1521498 or naltrexone werechosen adaptively to optimize the estimation of the dose-occupancyrelationship for each drug on the basis of data acquired from thepreceding examinations in the study. The administered dose range was0.4-100 mg for GSK1521498, and 2-50 mg for naltrexone. The maximum dosesadministered were equal to the maximum tolerated dose of GSK1521498determined in the first-in-human study and the standard clinical dose ofnaltrexone used for alcohol dependence. The times and doses of the twopost-dose [¹¹C]-carfentanil PET scans were chosen adaptively for eachsubject to optimize estimation of the relationship between plasmaconcentration and receptor occupancy. Post-dose [¹¹C]-carfentanil PETscans were acquired at 3-36 h after the administration of GSK1521498 andat 3-88 h after the administration of naltrexone. Post-dose fMRI scanswere acquired within 60 min of the first post-dose PET scan. Venousblood samples were collected at regular intervals throughout thescanning sessions. High-performance liquid chromatography/massspectrometry/mass spectrometry was used to estimate the plasmaconcentrations of GSK1521498, naltrexone, and the major metabolite ofnaltrexone, 6-β-naltrexol. Drug plasma concentration at the start ofeach PET scan was used to model the relationship between drugconcentrations and μ-opioid receptor occupancies. Carfentanil (methyl1-(2-phenylethyl)-4-(phenyl(propanoyl)amino)-4-piperidinecarboxylate 3S,5S; Advanced Biochemical Compounds, Radeberg, Germany), a potentselective μ-opioid receptor agonist, was labelled with carbon-11 using amodification of a previously described method implemented using asemiautomated Modular Lab Multifunctional Synthetic Module (Eckert &Ziegler, Berlin, Germany). The final product was reformulated in sterile0.9% saline containing ˜10% ethanol (v/v) and satisfied quality controlcriteria for specific activity and purity before being injectedintravenously as a slow bolus over ˜30 s. PET scanning was conducted inthree-dimensional mode using a Siemens Biograph 6 Hi-Rez PET-CT for thenaltrexone group and a Siemens Biograph 6 TruePoint PET-CT for theGSK1521498 group (Siemens Healthcare, Erlangen, Germany). A low-dose CTscan was acquired for attenuation correction before the administrationof the radiotracer. Dynamic PET data were acquired for 90 min after[¹¹C]-carfentanil injection, binned into 26 frames (durations: 8×15 s,3×60 s, 5×2 min, 5×5 min and 5×10 min), reconstructed using Fourierre-binning and a two-dimensional-filtered back projection algorithm andthen smoothed with a two-dimensional Gaussian filter (5 mm at full widthhalf maximum). Dynamic PET images were registered to each participant'sT1-weighted anatomical MRI volume and corrected for head motion usingSPM5 software (Wellcome Trust Centre for Neuroimaging). Pre-selectedregions of interests were defined bilaterally on the T1-weightedanatomical volume using an in-house atlas and applied to the dynamic PETdata to generate regional time-activity curves. The[¹¹C]-carfentanil-specific binding was quantified as binding potentialrelative to the non-displaceable compartment (BP_(ND))

${BP}_{ND} = \frac{f_{ND}B_{avail}}{K_{D}}$where f_(ND) is the free fraction of the radioligand in the brain, K_(D)is the affinity of [¹¹C]-carfentanil, and B_(avail) is the density ofthe available μ-opioid receptors. Regional [¹¹C]-carfentanil BP_(ND) wasestimated using a reference tissue model with the occipital cortex asthe reference region. Drug related occupancy of the μ-opioid receptorwas quantified as a reduction of [¹¹C]-carfentanil.

${Occupancy}_{Drug} = \frac{{BP}_{ND}^{Baseline} - {BP}_{ND}^{Drug}}{{BP}_{ND}^{Baseline}}$The affinity constant for each drug at the μ-opioid receptor (effectiveconcentration 50 (EC₅₀)) was estimated by fitting the plasmaconcentration measured at the start of the PET scan, C^(P) _(Drug), tothe estimated occupancy:

${Occupancy}_{Drug} = \frac{C_{Drug}^{P}}{C_{Drug}^{P} + {EC}_{50}}$

The use of a sensitive non-tomographic positron detecting system tomeasure the dose-response curve of naloxone in human brain has also beenreported. [¹¹C]Diprenorphine was administered to normal volunteers intracer amounts and, 30 min later, various bolus doses of naloxone weregiven (1.5-160 μg/kg) intravenously and change in [¹¹C]diprenorphinebinding monitored over the next 30 min. Approximately 13 μg/kg ofnaloxone (approximately 1 mg in an 80 kg man) was required to produce anestimated 50% receptor occupation, consistent with the clinical dose ofnaloxone used to reverse opiate overdose (0.4 mg-1.2 mg). Melichar etal., Naloxone displacement at opioid receptor sites measured in vivo inthe human brain. Eur J Pharmacol. 2003 Jan. 17; 459(2-3):217-9).

In some embodiments of the devices, kits, pharmaceutical formulations,and methods disclosed above, delivery of the therapeutically effectiveamount to the patient, provides occupancy at t_(max) of the opioidantagonist at the opioid receptors in the respiratory control center ofthe patient of greater than about 90%. In some embodiments, delivery ofthe therapeutically effective amount to the patient, provides occupancyat t_(max) of the opioid antagonist at the opioid receptors in therespiratory control center of the patient of greater than about 95%. Insome embodiments, delivery of the therapeutically effective amount tothe patient, provides occupancy at t_(max) of the opioid antagonist atthe opioid receptors in the respiratory control center of the patient ofgreater than about 99%. In some embodiments, delivery of thetherapeutically effective amount to the patient, provides occupancy att_(max) of the opioid antagonist at the opioid receptors in therespiratory control center of the patient of about 100%.

Also provided are embodiments wherein any embodiment described above maybe combined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

EXAMPLES Example 1 Pharmacokinetics and Safety of Intranasal Naloxone inHumans (Study 1)

A clinical trial was performed for which the primary objectives were todetermine the pharmacokinetics (PK) of 2 intranasal (IN) doses (2 mg and4 mg) of naloxone compared to a 0.4 mg dose of naloxone administratedintramuscularly (IM) and to identify an appropriate IN dose that couldachieve systemic exposure comparable to an approved parenteral dose. Thesecondary objectives were to determine the safety of IN naloxone,specifically with respect to nasal irritation (erythema, edema, anderosion).

Methodology: This was an inpatient open-label, randomized, 3-period,3-treatment, 6-sequence, crossover study involving 14 healthyvolunteers. Subjects were assigned to one of the 6 sequences with 2subjects in each sequence (2 sequences had 3 subjects). Each subjectreceived 3 naloxone doses, a single 2 mg IN dose (one spray of 0.1 mL of10 mg/mL solution in each nostril), a single 4 mg IN dose (2 sprays of0.1 mL per spray of 10 mg/mL solution in each nostril) and a single 0.4mg IM dose, in the 3 dosing periods (Table 1). Subjects stayed in theinpatient facility for 11 days to complete the entire study and weredischarged on the next day after the last dose. Subjects returned for afinal follow-up visit 3-5 days after discharge. After obtaining informedconsent, subjects were screened for eligibility to participate in thestudy including medical history, physical examination, clinicalchemistry, coagulation markers, hematology, infectious disease serology,urinalysis, urine drug and alcohol toxicology screen, vital signs andelectrocardiogram (ECG). On the day after clinic admission, subjectswere administered study drug in randomized order with a 4-day washoutperiod between doses until all three doses were administered. Blood wascollected for naloxone PK prior to dosing and approximately 2.5, 5, 10,15, 20, 30, 45, 60, 120, 180, 240, 300, 360, 480, and 720 min after thestart of study drug administration. On days of study drugadministration, a 12-lead ECG was performed approximately 60 min priorto dosing and at approximately 60 and 480 min post-dose. Vital signswere measured pre-dose and approximately 30, 60, 120, and 480 minpost-dose. On dosing days, the order of assessments was ECG, vitalsigns, then PK blood collection when scheduled at the same nominaltimes. ECG and vital signs were collected within the 10-min periodbefore the nominal time of blood collections. At screening, admission,discharge, and follow-up, ECG and vital signs were checked once per day.Vital signs were also checked once on the day after naloxoneadministration. Clinical laboratory measurements were repeated after thelast PK blood draw prior to clinic discharge. AEs were assessed byspontaneous reports by subjects, examination of the nasal mucosa,physical examination, vital signs, ECG, and clinical laboratoryparameters.

Main Criteria for Inclusion/Exclusion: Healthy volunteer adults with abody mass index (BMI) of 18-30 kg/m².

Investigational Product, Dose and Mode of Administration: Naloxone givenIN was at a dose of 2 mg (1 squirt in each nostril delivered 0.1 mL of10 mg/mL naloxone) and 4 mg (2 squirts in each nostril delivered 0.2mL/nostril at 10 mg/mL naloxone, using two devices). IN naloxone wasadministered using a Pfeiffer (Aptar) BiDose liquid device with thesubject in a fully supine position.

Duration of Treatment: Each IN and IM dose was administered once in eachsubject in random sequence.

Reference Therapy, Dose and Mode of Administration: Naloxone was givenIM at a dose of 0.4 mg in 1.0 mL with a 23-g needle as a singleinjection in the gluteus maximus muscle.

PK Evaluation: Blood was collected in sodium heparin containing tubesfor naloxone PK prior to dosing and 2.5, 5, 10, 15, 20, 30, 45, 60, 120,180, 240, 300, 360, 480, and 720 min after the start of study drugadministration. Non-compartmental PK parameters including C_(max),t_(max), AUC to infinity (AUC_(0-∞)), AUC to last measurableconcentration (AUC_(0-t)), t_(1/2), λ_(z), and apparent clearance (CL/F)were determined. Values of t_(1/2) were determined from the log-lineardecline in plasma concentrations from 2 to 6 or 8 h.

Safety Evaluation: Heart rate, blood pressure, and respiration rate wasrecorded before naloxone dosing and at approximately 30, 60, 120, and480 min after dosing. These vital signs and temperature were alsomeasured at screening, clinic intake, one day after each dosing sessionand at follow-up. A 12-lead ECG was obtained prior to and approximately60 and 480 min after each naloxone dose, as well as during screening,clinic intake, and follow-up. ECG and vital signs were taken within the10-min period before the nominal time for blood collections. AEs wererecorded from the start of study-drug administration until clinicdischarge. AEs were recorded relative to each dosing session to attemptto establish a relationship between the AE and type of naloxone doseadministered. An examination of the nasal passage was conducted at Day-1to establish eligibility and at pre-dose, 5 min, 30 min, 60 min, 4 h,and 24 h post naloxone administration to evaluate evidence of irritationto the nasal mucosa. Clinical laboratory measurements were done prior tothe first drug administration and on the day of clinic release.

Statistical Analysis of PK Parameters: C_(max), t_(max), and AUC for 2and 4 mg IN naloxone were compared with those for 0.4 mg IM naloxone.Within an ANOVA framework, comparisons of natural log (LN) transformedPK parameters (C_(max) and AUC) for IN versus IM naloxone treatmentswere performed. The 90% confidence interval (CI) for the ratio (IN/IM)of the least squares means of AUC and C_(max) parameters wasconstructed. These 90% CI were obtained by exponentiation of the 90%confidence intervals for the difference between the least squares meansbased upon a LN scale. In addition, dose adjusted values for AUCs andC_(max) based upon a 0.4 mg dose were calculated (Tables 4-7). Therelative extent of absorption (relative bioavailability, F_(rel)) ofintranasal (IN versus IM) was estimated from the dose-corrected AUCs.

Statistical Analysis of Adverse Events: AEs were coded using the MedicalDictionary for Regulatory Activities (MedDRA), version 19. Preferredterms and are grouped by system, organ, class (SOC) designation. AEs arepresented as a listing including the start date, stop date, severity,relationship, outcome, and duration.

Pharmacokinetics Results: The mean dose delivered for the 2 mg INnaloxone dose was 1.71 mg (range 1.50 mg to 1.80 mg) and for the 4 mg INnaloxone dose it was 3.40 mg (range 2.93 mg to 3.65 mg). This was 84-85%of the target dose. The overall % coefficient of variation (% CV) forthe delivered dose from all 42 devices was 6.9% (Table 9). Preparationtime of the IN doses took less than one third of the time to prepare theIM injection (70 seconds for the IM injection and 20 seconds for the INadministration) (Table 8). The time to prepare the IM injection did notinclude loading the syringe. Since the one purpose of the study was todetermine if peak naloxone plasma concentrations (C_(max)) and AUCsfollowing IN 2 mg and IN 4 mg administrations were equivalent to, orgreater than IM 0.4 mg dosing, AUCs and C_(max) values were comparedwithout considering the dose difference among treatments. The C_(max),AUC_(0-t), and AUC_(0-∞) for both the 2 mg IN and 4 mg IN doses werestatistically significantly greater than those for the 0.4 mg IM dose(p<0.001). The geometric least square means for C_(max) were 2.18 ng/mL,3.96 ng/mL, and 0.754 ng/mL for IN 2 mg, IN 4 mg and IM 0.4 mg,respectively. The geometric least square means for AUC_(0-∞) were 3.32ng·h/mL, 5.47 ng·h/mL and 1.39 ng·h/mL for IN 2 mg, IN 4 mg and IM 0.4mg respectively. The geometric least squares mean ratios for IN 2 mg/IM0.4 mg were 290% for C_(max) and 239% for AUC_(0-∞). The ratios for IN 4mg/IM 0.4 mg were 525% for C_(max) and 394% for AUC_(0-∞). There were nostatistically significant differences between the routes and doses withrespect to t_(max), suggesting peak effects would occur at similar timesfor all treatments. However, the mean t_(max) values did trend lower forthe IN route versus IM, and for 4 mg IN versus 2 mg IN. (See Table 2).In comparing the extent of systemic absorption of IN to IM dosing, theF_(rel) estimates were 55.7% and 46.3% for IN 2 mg and 4 mg,respectively. See Table 3.

Safety Results: No erythema, edema, erosion, or other sign was observedin the nasal cavity prior to or after any IN administration of naloxoneat 2 and 4 mg to both nostrils. One subject experienced mild transient(over 3 min) pharyngeal pain coincident with the application of the 2 mgIN dose. This pain resolved spontaneously. Vital signs, ECG, andclinical laboratory parameters did not reveal any clinically noteworthychanges after naloxone administration. There was no evidence of QTcFprolongation.

TABLE 1 Order of Naloxone Doses and Route of Administration for eachSubject. Sub- ject Sequence Dosing Session Dosing Session Dosing Session# ID # #1 Day 1 #2 Day 5 #3 Day 9 1 102 5 4 mg IN 2 mg IN 0.4 mg IM 2107 6 0.4 mg IM 4 mg IN 2 mg IN 3 112 1 2 mg IN 4 mg IN 0.4 mg IM 4 1173 0.4 mg IM 2 mg IN 4 mg IN 5 120 1 2 mg IN 4 mg IN 0.4 mg IM 6 123 2 4mg IN 0.4 mg IM 2 mg IN 7 127 3 0.4 mg IM 2 mg IN 4 mg IN 8 128 5 4 mgIN 2 mg IN 0.4 mg IM 9 133 2 4 mg IN 0.4 mg IM 2 mg IN 10 113 4 2 mg IN0.4 mg IM 4 mg IN 11 114 1 2 mg IN 4 mg IN 0.4 mg IM 12 119 6 0.4 mg IM4 mg IN 2 mg IN 13 125 4 2 mg IN 0.4 mg IM 4 mg IN 14 135 5 4 mg IN 2 mgIN 0.4 mg IM

TABLE 2 Summary of Naloxone Pharmacokinetic Parameters FollowingNaloxone as 0.4 mg Intramuscular (IM), 2 mg Intranasal (IN), and 4 mg INAdministrations. 0.4 mg IM 2 mg IN 4 mg IN Parameter Mean % CV Mean % CVMean % CV Dose (mg) 0.400 — 1.714 5.7 3.403 5.7 C_(max) (ng/mL) 0.76527.6 2.32 41.2 4.55 63.7 t_(max) (min) 20.34 36.1 19.98 31.0 18.42 33.6AUC_(0-t) 1.38 19.9 3.41 29.5 5.63 27.6 ng · h/mL AUC_(0-∞) 1.42 19.23.44 29.3 5.68 27.6 (ng · h/mL) λ_(z) (1/h) 0.593 16.6 0.588 0.572 8.010.2 t_(1/2) (h) 1.21 20.1 1.19 8.3 1.22 10.2

TABLE 3 Summary of Naloxone Pharmacokinetic Parameters FollowingNaloxone as 0.4 mg Intramuscular (IM), 2 mg Intranasal (IN), and 4 mg INAdministrations with Dose Normalized to 0.4 mg. 0.4 mg IM 2 mg IN 4 mgIN Parameter Mean % CV Mean % CV Mean % CV AUC_(0-t/D) 1.38 19.9 0.79628.7 0.667 29.4 ng · h/mL AUC_(0-∞/D) 1.42 19.2 0.804 29.3 ng · h/mLF_(rel) 0.571 24.5 0.475 25.3

TABLE 4 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 2 mg to IMNaloxone at a Dose of 0.4 mg with No Dose Adjustment. GLSM GLSM GLSM 2mg 0.4 mg Ratio 90% CI of Parameter IN IM IM/IN % Ratio p-value C_(max)(ng/mL) 2.18 0.754 290 237-353 <0.001 t_(max) (h) 0.333 0.308 — — 1.000AUC_(0-t) 3.28 1.35 243 219-270 <0.001 (ng · h/mL) AUC_(0-∞) 3.32 1.39239 215-264 <0.001 (ng · h/mL) t_(1/2) (h) 1.18 1.19 102 94.0-111 0.6507

TABLE 5 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 4 mg to IMNaloxone at a Dose of 0.4 mg with No Dose Adjustment. GLSM GLSM GLSM 4mg 0.4 mg Ratio 90% CI of Parameter IN IM IM/IN % Ratio p-value C_(max)(ng/mL) 3.96 0.754 525 431-640 <0.001 AUC_(0-t) (ng · h/mL) 5.41 1.35401 361-445 <0.001 AUC_(0-∞) (ng · h/mL) 5.47 1.39 394 355-436 <0.001t_(1/2) (h) 1.22 1.19 102 94.0-111  0.651

TABLE 6 Statistical Comparison of Geometric Least Squares Mean (GLSM) ofPharmacokinetic Parameters for IN Naloxone at a Dose of 2 mg to IMNaloxone at a Dose of 0.4 mg with Dose Adjustment to 0.4 mg. GLSM GLSMGLSM 2 mg 0.4 mg Ratio 90% CI of Parameter IN IM IM/IN % Ratio p-valueC_(max/D) (ng/mL) 0.510 0.755 67.6 55.3-82.7 0.0028 t_(max) (h) 0.3330.308 — — 1.000 AUC_(0-t/D) 0.767 1.35 56.8 50.8-63.4 <0.001 (ng · h/mL)AUC_(0-∞/D) 0.775 1.39 55.7 50.0-62.1 <0.001 (ng · h/mL) t_(1/2) (h)1.18 1.19 99.3 91.3-108  0.8963

TABLE 7 Statistical Comparison of Comparison of Geometric Least SquaresMean (GLSM) Pharmacokinetic Parameters for IN Naloxone at a Dose of 4 mgto IM Naloxone at a Dose of 0.4 mg with Dose Adjustment to 0.4 mg. GLSMGLSM GLSM 4 mg 0.4 mg Ratio 90% CI of Parameter IN IM IM/IN % Ratiop-value C_(max/D) (ng/mL) 0.466 0.755 61.7 50.5-75.5 <0.001 t_(max) (h)0.292 0.308 — — 0.418 AUC_(0-t/D) 0.637 1.35 47.2 42.2-52.7 <0.001 (ng ·h/mL) AUC_(0-∞/D) 0.644 1.39 46.3 41.5-51.6 <0.001 (ng · h/mL) t_(1/2)(h) 1.22 1.19 102 94.0-111  0.651

TABLE 8 Time to Prepare the IM and IN Doses for Administration. Time(seconds) IM Dose 2 mg IN Dose 4 mg IN Dose N 14 14 14 Mean 70 19 23 SD10 4 3 Median 73 19 23 Minimum 50 15 18 Maximum 82 30 28

TABLE 9 Estimated IN Dose Delivered (mg). 4 mg Dose 2 mg Dose FirstSecond All Devices Total Device Device Total Total N 14 14 14 14 42 Mean1.697 1.682 1.687 3.369 1.689 SD 0.097 0.156 0.092 0.193 0.116 % CV 5.79.3 5.4 5.7 6.9 Median 1.708 1.711 1.704 3.410 1.710 Minimum 1.481 1.3151.506 2.898 1.315 Maximum 1.838 1.824 1.803 3.616 1.838

Example 2 Pharmacokinetics and Safety of Intranasal Naloxone in Humans(Study 2)

A second study was undertaken to determine the pharmacokinetics (PK) andbioavailability of intranasally-delivered naloxone compared tointramuscularly-injected naloxone.

Objectives. Specifically, the study had several objectives. The firstwas to determine the pharmacokinetics (i.e., the C_(max), t_(max),AUC_(0-inf) and AUC_(0-t)) of 4 intranasal doses—2 mg, 4 mg (2nostrils), 4 mg (1 nostril), and 8 mg (2 nostrils)—of naloxone comparedto a 0.4 mg dose of naloxone administrated IM and to identify anappropriate IN dose that could achieve systemic exposure comparable toan approved parenteral dose. The second was to determine thepharmacokinetics of two different concentrations (20 mg/mL and 40 mg/mL)of IN naloxone. The third was to determine the safety of IN naloxone,including adverse events, vital signs, and clinical laboratory changes,specifically with respect to nasal irritation (erythema, edema, anderosion).

Design. The study was an inpatient open-label, randomized, 5-period,5-treatment, 5-sequence, crossover study involving approximately 30healthy volunteers, randomized to have at least 24 subjects who completeall study drug administrations and blood collections for PK assessments.Subjects were assigned to one of the 5 sequences and there were 6subjects in each. Each subject received 5 naloxone treatments during the5 dosing periods: a single 2 mg IN dose (one 0.1 mL spray of a 20 mg/mLsolution in one nostril), a 4 mg IN dose (one 0.1 mL spray of a 20 mg/mLsolution in each nostril), a single 4 mg IN dose (one 0.1 mL spray of a40 mg/mL solution in one nostril), a single 8 mg IN dose (one 0.1 mLspray of a 40 mg/mL solution in each nostril), and a single 0.4 mg IMdose. Subjects stayed in an inpatient facility for 18 days to completethe entire study and were discharged on the next day after the lastdose. Subjects returned for a final follow-up visit 3 to 5 days afterdischarge.

After obtaining informed consent, subjects were screened for eligibilityto participate in the study including medical history, physicalexamination, clinical chemistry, coagulation markers, hematology,infectious disease serology, urinalysis, urine drug and alcoholtoxicology screen, vital signs and ECG.

Inclusion criteria were: men or women 18 to 55 years of age, inclusive;written informed consent; BMI ranging from 18 to 30 kg/m2, inclusive;adequate venous access; no clinically significant concurrent medicalconditions; agreement to use a reliable double-barrier method of birthcontrol from the start of screening until one week after completing thestudy (oral contraceptives are prohibited); and agreement not to ingestalcohol, drinks containing xanthine >500 mg/day, orgrapefruit/grapefruit juice, or participate in strenuous exercise 72hours prior to admission through the last blood draw of the study.

Exclusion criteria were: any IN conditions including abnormal nasalanatomy, nasal symptoms (i.e., blocked and/or runny nose, nasal polyps,etc.), or having a product sprayed into the nasal cavity prior to drugadministration; taking prescribed or over-the-counter medications,dietary supplements, herbal products, vitamins, or recent use of opioidanalgesics for pain relief (within 14 days of last use of any of theseproducts); positive urine drug test for alcohol, opioids, cocaine,amphetamine, methamphetamine, benzodiazepines, tetrahydrocannabinol(THC), barbiturates, or methadone at screening or admission; previous orcurrent opioid, alcohol, or other drug dependence (excluding nicotineand caffeine), based on medical history; subject consumes greater than20 cigarettes per day on average, in the month prior to screening, orwould be unable to abstain from smoking (or use of anynicotine-containing substance) for at least one hour prior to and 2hours after naloxone dosing; on standard 12-lead ECG, a QTcFinterval >440 msec for males and >450 msec for females; significantacute or chronic medical disease in the judgment of the investigator; alikely need for concomitant treatment medication during the study;donated or received blood or underwent plasma or platelet apheresiswithin the 60 days prior to the day before study commencement; femalewho is pregnant, breast feeding, or plans to become pregnant during thestudy period or within one week after naloxone administration; positivetest for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody(HCVAb) or human immunodeficiency virus antibody (HIVAb) at screening;and current or recent (within 7 days prior to screening) upperrespiratory tract infection.

Naloxone for IM injection manufactured by Hospira was obtained from alicensed distributor at a concentration of 0.4 mg/mL and was given IM ata dose of 0.4 mg in 1.0 mL with a 23-g needle as a single injection inthe gluteus maximus muscle. Naloxone for IN administration was obtainedfrom Lightlake Therapeutics, Inc., London, United Kingdom at twoconcentrations of 20 mg/mL and 40 mg/mL, and was given as doses of 2 mg(one 0.1 mL spray of the 20 mg/mL formulation in one nostril), 4 mg (two0.1 mL sprays of the 20 mg/mL formulation in two nostrils), 4 mg (one0.1 mL spray of the 40 mg/mL formulation in one nostril) and 8 mg (two0.1 mL sprays of the 40 mg/mL formulation in two nostril). IN naloxonewas administered using an Aptar single dose device with the subject in afully supine position. Subjects were to be instructed to not breathethrough the nose when the IN dose of naloxone was administered.

On the day after clinic admission, subjects were administered study drugin randomized order with a 4-day washout period between doses until all5 treatments were administered. Blood was collected for naloxone PKprior to dosing and approximately 2.5, 5, 10, 15, 20, 30, 45, 60, 120,180, 240, 300, 360, 480 and 720 minutes after the start of study drugadministration, into sodium heparin containing tubes. On days of studydrug administration, a 12-lead ECG was performed approximately 60minutes prior to dosing and at approximately 60 and 480 minutespost-dose. Vital signs were measured pre-dose and approximately 30, 60,120, and 480 minutes post-dose. On dosing days, the order of assessmentswere ECG, vital signs, then PK blood collection when scheduled at thesame nominal times. The target time of the PK blood collection wasconsidered the most important, and if the collection was more than ±1minute from the scheduled time for the first 60 minutes of collectionsor more than ±5 minutes for the scheduled time points thereafter, thiswas considered a protocol deviation. ECG and vital signs were collectedwithin the 10 minute period before the nominal time of bloodcollections. At screening, admission, discharge, and follow-up, ECG andvital signs were checked once per day. Vital signs were also checkedonce on the day after naloxone administration. Clinical laboratorymeasurements were repeated after the last PK blood draw prior to clinicdischarge. Adverse events were assessed by spontaneous reports bysubjects, by examination of the nasal mucosa, by measuring vital signs,ECG, and clinical laboratory parameters.

Results are shown below in Table 10, which sets forth the mean from 28healthy subjects (and SD, in parentheses) plasma concentrations ofnaloxone following single intranasal administrations and anintramuscular injection, and in FIGS. 3 and 4.

TABLE 10 Mean results from 28 healthy subjects. One Spray - Two Sprays -One Spray - Two Sprays - Time 2 mg 4 mg 4 mg 8 mg (min) 2% (w/v) IN 2%(w/v) IN 4% (w/v) IN 4% (w/v) IN 0.4 mg IM 0 0.000 (0.000) 0.000 (0.000)0.000 (0.000) 0.000 (0.000) 0.000 (0.000) 2.5 0.175 (0.219) 0.725(0.856) 0.280 (0.423) 0.880 (1.21) 0.081 (0.135) 5 0.882 (0.758) 2.68(2.65) 1.50 (1.76) 3.73 (4.02) 0.305 (0.336) 10 2.11 (1.33) 4.60 (2.59)3.24 (2.21) 7.61 (5.28) 0.566 (0.318) 15 2.74 (1.07) 5.56 (2.20) 4.00(2.24) 8.02 (3.60) 0.678 (0.312) 20 2.89 (1.14) 5.82 (1.74) 4.57 (2.30)8.06 (2.56) 0.747 (0.271) 30 2.52 (0.810) 5.15 (1.70) 4.50 (1.93) 7.89(1.95) 0.750 (0.190) 45 2.17 (0.636) 4.33 (1.16) 4.03 (1.57) 6.84 (1.69)0.689 (0.171) 60 1.88 (0.574) 3.69 (0.887) 3.35 (1.17) 5.86 (1.40) 0.610(0.143) 120 0.823 (0.335) 1.63 (0.626) 1.57 (0.773) 2.86 (0.927) 0.354(0.107) 180 0.390 (0.146) 0.800 (0.253) 0.771 (0.412) 1.42 (0.487) 0.227(0.082) 240 0.215 (0.100) 0.452 (0.225) 0.412 (0.215) 0.791 (0.275)0.135 (0.058) 300 0.117 (0.051) 0.243 (0.123) 0.246 (0.143) 0.431(0.166) 0.074 (0.047) 360 0.068 (0.030) 0.139 (0.067) 0.146 (0.081)0.257 (0.104) 0.040 (0.022) 480 0.031 (0.014) 0.068 (0.033) 0.065(0.038) 0.122 (0.052) 0.013 (0.015) 720 0.009 (0.009) 0.027 (0.013)0.026 (0.019) 0.053 (0.025) 0.001 (0.003)

For pharmacokinetic analysis, plasma was separated from whole blood andstored frozen at ≧−20° C. until assayed. Naloxone plasma concentrationswere determined by liquid chromatography with tandem mass spectrometry.Conjugated naloxone plasma concentrations may also be determined.Non-compartmental PK parameters including C_(max), t_(max), AUC_(0-inf),AUC_(0-t), t_(1/2), λ_(z), and apparent clearance (CL/F) weredetermined. Pharmacokinetic parameters (C_(max), C_(max), and AUCs) forIN naloxone were compared with those for IM naloxone. t_(max) was fromthe time of administration (spraying into the nasal cavity or IMinjection). Dose adjusted values for AUCs and C_(max) were thencalculated, and the relative extent of intranasal absorption (IN versusIM) estimated from the dose-corrected AUCs. Within an ANOVA framework,comparisons of In-transformed PK parameters (C_(max) and AUC) forintranasal versus IM naloxone treatments were performed. The 90%confidence interval for the ratio (IN/IM) of the geometric least squaresmeans of AUC and C_(max) parameters were constructed for comparison ofeach treatment with IM naloxone. These 90% CIs were obtained byexponentiation of the 90% confidence intervals for the differencebetween the least squares means based upon an In scale.

Results are shown below in Table 11, which sets forth the mean plasma PKparameters from 28 healthy subjects (and % CV, in parentheses) ofnaloxone following single intranasal administrations and anintramuscular injection, and in Table 12, which sets forth the same PKparameters split between the 12 female and 16 male healthy subjects.Results from a replication study conducted according to substantiallythe same experimental protocols are shown in Table 11 below.

TABLE 11 Mean plasma PK parameters from 28 healthy subjects. One Spray -Two Sprays - One Spray - Two Sprays - Parameter 2 mg 4 mg 4 mg 8 mg(units) 2% (w/v) IN 2% (w/v) IN 4% (w/v) IN 4% (w/v) IN 0.4 mg IMC_(max) (ng/ml) 3.11 (36.3) 6.63 (34.2) 5.34 (44.1) 10.3 (38.8) 0.906(31.5) C_(max) per mg 1.56 (36.3) 1.66 (34.2) 1.34 (44.1) 1.29 (38.8)2.26 (31.5) (ng/mL) t_(max) (h)^(a) 0.33 (0.25, 0.33 (0.08, 0.50 (0.17,0.33 (0.17, 0.42 (0.08, (median, range) 1.00) 0.50) 1.00) 1.00) 2.00)AUC_(t) (ng · mL/h) 4.81 (30.3) 9.82 (27.3) 8.78 (37.4) 15.9 (23.6) 1.79(23.5) AUC_(inf) 4.86 (30.1) 9.91 (27.1) 8.87 (37.2) 16.1 (23.3) 1.83(23.0) (ng · mL/h) AUC_(inf) per mg 2.43 (30.1) 2.48 (27.1) 2.22 (37.2)2.01 (23.3) 4.57 (23.0) (ng · mL/h) Lambda z (hr⁻¹)^(b) 0.3685 0.29730.3182 0.3217 0.5534 Half-life (h)^(b) 1.70 2.09 2.00 1.91 1.19 AUC %1.09 (41.9) 1.01 (53.9) 1.06 (52.5) 1.04 (78.1) 2.32 (54.1) ExtrapolateCL/F (L/h)  441 (24.5)  426 (22.3)  502 (31.2)  521 (21.7)  230 (22.4)Relative BA (%) 53.8 (22.2) 55.3 (22.2) 49.2 (30.6) 45.3 (25.1) 100 vs.IM

TABLE 12 Mean plasma PK parameters from 28 healthy subjects. One Two OneTwo Parameter 2% (w/v) IN 2% (w/v) IN 4% (w/v) IN 4% (w/v) IN 0.4 mg IM(units) Female Male Female Male Female Male Female Male Female MaleC_(max) (ng/ml) 2.79 3.35 6.62 6.64 5.12 5.51 9.52 10.9 1.06 0.792C_(max) per mg 1.39 1.68 1.66 1.66 1.28 1.38 1.19 1.36 2.64 1.98 (ng/mL)t_(max) (h)^(a) 0.33 0.33 0.33 0.25 0.50 0.50 0.29 0.42 0.33 0.50AUC_(t) 4.73 4.87 9.81 9.82 7.98 9.38 14.8 16.8 1.83 1.75 (ng · mL/h)AUC_(inf) 4.78 4.93 9.91 9.92 8.06 9.48 15.0 16.9 1.88 1.79 (ng · mL/h)AUC_(inf) per mg 2.39 2.46 2.48 2.48 2.01 2.37 1.87 2.12 4.69 4.47 (ng ·mL/h) Lambda z 0.3978 0.3492 0.2796 0.3122 0.2946 0.3386 0.2994 0.34070.6140 0.5152 (hr⁻¹)^(b) Half-life (h) ^(b) 1.58 1.80 2.18 2.03 2.121.93 1.90 1.91 1.08 1.28 AUC % 0.971 1.19 0.986 1.02 0.970 1.12 1.120.992 2.31 2.32 Extrapolate CL/F (L/h) 449 434 419 431 555 462 558 494222 236

In the tables above, the notation a indicates median (range) isdisclosed, and the notation b indicates harmonic mean is disclosed.

TABLE 13 Geometric mean pharmacokinetic parameters (CV %) followingintranasal spray or intramuscular injection. One Spray Two Sprays OneSpray Two Sprays One Injection Parameter 2% (w/v) IN 2% (w/v) IN 4%(w/v) IN 4% (w/v) IN 0.4 mg IM λz (1/h) 0.382 (34.9)  0.310 (34.5) 0.334 (29.5)  0.330 (32.4)  0.557 (25.9)  t_(1/2) (h) 1.81 (34.9) 2.23(34.5) 2.08 (29.5) 2.10 (32.4) 1.24 (25.9) t_(max) (h)* 0.33 0.33 0.500.33 0.38 (0.25, 1.00) (0.17, 0.57) (0.17, 1.00) (0.17, 1.00) (0.08,2.05) C_(max) (ng/mL) 2.92 (34.3) 6.20 (31.9) 4.83 (43.1) 9.70 (36.0)0.877 (30.5) C_(max)/Dose 1.46 (34.3) 1.55 (31.9) 1.21 (43.1) 1.21(36.0) 2.19 (30.5) (ng/mL/mg) AUC_(0-t) 4.51 (27.2) 9.32 (24.0) 7.87(37.4) 15.3 (23.0) 1.72 (22.9) (h * ng/mL) AUC_(0-t)/Dose 2.25 (27.2)2.33 (24.0) 1.97 (37.4) 1.91 (23.0) 4.29 (22.9) (h * ng/mL/mg) AUC_(0-∞)4.56 (26.9) 9.43 (24.0) 7.95 (37.3) 15.5 (22.7) 1.76 (22.6) (h * ng/mL)AUC_(0-∞)/Dose 2.28 (26.9) 2.36 (24.0) 1.99 (37.3) 1.93 (22.7) 4.40(22.6) (h * ng/mL/mg) AUC % 1.06 (56.5) 0.935 (60.1) 0.965 (53.5) 0.963(69.3) 2.18 (57.5) extrapolated CL/F (L/h)  438 (26.9)  424 (24.0)  503(37.3)  518 (22.7)  227 (22.6) Relative BA 51.9 (21.7) 53.6 (22.5) 46.7(31.4) 43.9 (23.8) 100 (%) C_(max)/Dose 66.6 (41.4) 70.7 (37.7) 56.6(47.5) 55.3 (41.4) 100 Ratio (IN vs. IM) (%) *Values in parenthesesindicate minimum and maximum, not CV %.

AEs were coded using the MedDRA, v. 19 preferred terms and grouped bysystem, organ, class (SOC) designation. Separate summaries will beprovided for the 5 study periods: after the administration of each doseof study drug up until the time of the next dose of study drug or clinicdischarge. Listings of each individual AE including start date, stopdate, severity, relationship, outcome, and duration were provided.Results are given below in Tables 14 and 15. Table 14 shows the eventsrelated to nasal irritation—erythema, edema, other, and total—observedin the nasally-treated group. Nasal irritation did not appear to bepositively related to the dose of naloxone given.

TABLE 14 Events related to nasal irritation. Treatment Erythema EdemaOther Total 2 mg (2% w/v, one spray) 4 2 1 7 4 mg (2% w/v, two sprays) 10 0 1 4 mg (4% w/v, one spray) 1 2 0 3 8 mg (4% w/v, two sprays) 0 1 0 1

Table 15 shows additional events related to administration eithernasally or intramuscularly. Overall, few adverse events were reported.

TABLE 15 Naloxone intranasal adverse events. 0.4 mg Intramuscular DoseDizziness 1 Headache 1 Nausea 1 2 mg (2% w/v, one spray) Nasal Pain 1 8mg (4% w/v, two sprays) Headache 1

Additionally, vital signs, ECG, and clinical laboratory parameters didnot reveal any clinically noteworthy changes after naloxoneadministration. There was no evidence of QTcF prolongation.

Example 3 Naloxone Nasal Spray Formulations and Stability

Naloxone has been formulated as a disposable Luer-Jet Luer-lockpre-filled injectable syringe. Although not approved as a combinedproduct, this formulation is sometimes combined with an nasal atomizerkit product, comprising 1 mg/ml naloxone hydrochloride as an activeagent, 8.35 mg/ml NaCl as an isotonicity agent, HCl q.s. to target pH,and purified water q.s. to 2.0 ml. Benzalkonium chloride may be added asa preservative and supports the stability of a multi-dose product. Suchsyringes, while functional, can be difficult to use by untrainedpersonnel, and deliver a large volume of solution.

Examples of a 10 mg/mL formulation are given below in Table 16.

TABLE 16 10 mg/mL naloxone intranasal formulation. Ingredient Quantityper unit Function Naloxone hydrochloride  10 mg/ml Active ingredientSodium chloride 7.4 mg/ml Isotonicity agent Hydrochloric acid q.s. totarget pH Acidifying agent Benzalkonium chloride 0.1 mg/mlPreservative/Enhancer Purified water q.s. Solvent

Literature data has indicated that naloxone is sensitive toenvironmental factors, such as air, light and colors in certain vials,which may induce a risk for degradation. Consequently disodium edetatewas added to the above formulation.

Pharmaceutical compositions comprising naloxone hydrochloride (1, 2, or4% w/v, i.e., 10, 20, or 40 mg/mL) were stored at 25° C. and 60%relative humidity or 40° C. and 75% relative humidity in upright clearglass vials (200 μL) stoppered with a black plunger. The 2% and 4% (w/v)compositions were also tested at 40° C. and 75% relative humidity. Vialsof the 1% (w/v) compositions were either nude (Batch 1), or mounted inthe Pfeiffer BiDose device (Batch 2). In addition to naloxonehydrochloride, the pharmaceutical compositions further comprised water,benzalkonium chloride, and disodium edetate. The vials were assayed at0, 1, 3, 6, 9, and/or 12 months for naloxone content using ahigh-pressure liquid chromatography method. Naloxone was analyzed ateach stability station using a validated (as per the InternationalConference on Harmonisation Guidance Q2(R1) (ICH Q2(R1)) reverse phasehigh pressure liquid chromatography (RP-HPLC) method and ultraviolet(UV) detection. The chromatographic system used a C6-phenylchromatography column at a flow rate of 0.8 mL/min and a columntemperature of 40° C. The injection volume was 10 μL; the gradient A/B60/40 to 40/60; the mobile phase A 25 mM sodium phosphate at pH 6.8; themobile phase B: 100% acetonitrile. The ultra-violet detector wavelengthwas 229 nm and the runtime was 20 min. The assay data in Table 18 weregenerated over the course of development. The 25° C./60% RH experimentswere conducted with clinical batches and the 40° C./75% RH experimentsused later manufactured registration or stability batches. It is evidentfrom the results of the study, reported as a percentage of the labelclaim in Tables 17 and 18 below, that these pharmaceutical compositionsare storage-stable for at least 9-12 months at 25° C. and 60% relativehumidity.

TABLE 17 1% (w/v) Naloxone storage stability. Time (months) Batch 0 3 69 12 1 99.3 100.1 100.8 101.2 97.9 2 99.5 102.8 99.4 98.6 ND

TABLE 18 2% and 4% (w/v) Naloxone storage stability. Temp. & Naloxonerelative conc. Naloxone stability (assay % of target amount) humidity (%w/v) Initial 1 month 3 month 6 month 12 month 40° C. 2 103.5 103 99.8100.4 75% RH 4 105.8 103.4 102 100.7 25° C. 2 101.2 104.8 102.4 101.660% RH 4 101.8 101.3 102.9 101.9

Examples with the 20 and 40 mg/mL formulations are given below in Table19, along with an example of permitted variation as part of the totalformulation. Subsequent modifications were able to reduce thedose-to-dose variation further still, even after six- to twelve-monthstorage (Table 20).

TABLE 19 Twelve month naloxone storage stability. Concentration 20 mg/ml40 mg/ml Quantity Quantity per unit per unit Quantity dose Quantity doseProduct Component per ml (100 μl) per ml (100 μl) Variation Naloxone HCl22.0 mg  2.2 mg 44.0 mg  4.4 mg 90.0-110.0 dihydrate (20.0 mg)  (2.0 mg)(40.0 mg)  (4.0 mg) (corresponding to naloxone HCl) Benzalkonium 0.1 mg0.01 mg  0.1 mg 0.01 mg  90.0-110.0 chloride Disodium edetate 2.0 mg 0.2mg 2.0 mg 0.2 mg 80.0-120.0 Sodium chloride 7.4 mg 0.74 mg 7.4 mg 0.74mg  Hydrochloric Adjust to Adjust to Adjust to Adjust to pH 3.5-5.5acid, dilute pH 4.5 pH 4.5 pH 4.5 pH 4.5 Purified water q.s. ad 1.0 mlq.s. ad 100 μl q.s. ad 1.0 ml q.s. ad 100 μl

TABLE 20 Six month naloxone storage stability. Sample age 1 month 3month 6 month Initial (% TD) (% TD) (% TD) (% TD) 2% (w/v) Storedupright at Uniform dose 1) 102.0% 1) 99.9% 1) 99.5% 1) 101.7% 25° C.,60% delivery 2) 96.7% 2) 103.7% 2) 101.6% 2) 100.4% relative humidity 3)101.6% 3) 102.7% 3) 98.5% 3) 99.8% 4) 101.7% 4) 101.7% 4) 100.0% 4)97.2% 5) 98.5% 5) 95.8% 5) 99.4% 5) 100.5% 6) 101.0% 6) 98.6% 6) 96.6%6) 96.8% 7) 100.6% 7) 98.9% 7) 102.5% 7) 98.3% 8) 101.4% 8) 98.7% 8)97.0% 8) 102.0% 9) 100.0% 9) 99.2% 9) 102.6% 9) 96.9% 10) 99.2% 10)100.5% 10) 100.6% 10) 102.4% Avg. 100.3% 100.1% 99.9% 99.7% Mean pump101.3 mg 101.0 mg 100.8 mg 100.6 mg delivery 3 cm mean 1.180 1.230 1.5221.516 ovality ratio 6 cm mean 1.383 1.386 1.687 1.764 ovality ratio 3 cmspray 65.40 μm 55.84 μm 73.07 μm 69.13 μm mean Dv(90) 3 cm spray 1.4291.300 1.572 1.447 mean span 3 cm spray 1.342% 1.982% 1.637% 0.269% mean% <10 μm 6 cm spray 62.01 μm 65.60 μm 66.95 μm 64.81 μm mean Dv(90) 6 cmspray 1.103 1.087 1.210 1.155 mean span 6 cm spray 1.714% 1.799% 1.625%1.634% mean % <10 μm 2% (w/v) Stored inverted at Avg. % TD of ten 100.3%99.9% 98.3% 100.0% 25° C. 60% actuations relative humidity Mean pump101.3 mg 100.8 mg 99.2 mg 100.9 mg delivery 3 cm mean 1.180 1.210 1.2141.159 ovality ratio 6 cm mean 1.383 1.421 1.351 1.442 ovality ratio 3 cmspray 65.40 μm 69.60 μm 68.33 μm 70.05 μm mean Dv(90) 3 cm spray 1.4291.473 1.509 1.491 mean span 3 cm spray 1.342% 1.543% 1.637% 1.218% mean% <10 μm 6 cm spray 62.01 μm 62.96 μm 65.51 μm 69.02 μm mean Dv(90) 6 cmspray 1.103 1.133 1.217 1.171 mean span 6 cm spray 1.714% 1.828% 1.400%1.752% mean % <10 μm 6 month 12 month Initial (% TD) (% TD) (% TD) 4%(w/v) Stored upright at Uniform dose 1) 100.2% 1) 98.6% 1) 99.4% 25° C.,60% delivery 2) 97.3% 2) 98.2% 2) 107.1% relative humidity 3) 96.1% 3)98.1% 3) 103.3% 4) 99.4% 4) 101.5% 4) 98.6% 5) 98.8% 5) 96.4% 5) 99.1%6) 98.3% 6) 98.0% 6) 103.6% 7) 100.2% 7) 97.7% 7) 102.7% 8) 101.3% 8)97.9% 8) 100.8% 9) 99.8% 9) 97.3% 9) 101.5% 10) 99.7% 10) 98.4% 10)100.1% Avg. 99.11% 98.21% 101.62% Mean pump 100.2 mg 103.1 mg delivery 3cm mean 1.511 ovality ratio 6 cm mean 1.435 ovality ratio 3 cm spray90.56 μm mean Dv(90) 3 cm spray 1.680 mean span 3 cm spray 1.135% mean %<10 μm 6 cm spray 66.27 μm mean Dv(90) 6 cm spray 1.137 mean span 6 cmspray 1.825% mean % <10 μm

The naloxone hydrochloride nasal spray above is an aqueous solutionwhich may be presented in a Type I glass vial closed with a chlorobutylrubber plunger which in turn is mounted into a unit-dose nasal spraydevice (such as an Aptar UDS liquid UnitDose device). The solutionshould be a clear and colorless or slightly yellow liquid. In certainembodiments, the device is a non-pressurized dispenser delivering aspray containing a metered dose of the active ingredient. In certainembodiments, each delivered dose contains 100 μL.

The droplet size distribution (was investigated as a function of deviceage and storage according to established and validated testing methods.A Malvern Spray Tec 2.0 with automated device actuation was used fordetermining the droplet size distribution of Naloxone Nasal Spray.Spraytec laser diffraction system allows measurement of spray dropletsize distributions in real-time. Droplet Size Distribution: As reportedfrom the Malvern Spraytec, the distribution is a cumulative volumedistribution characterized by the Dv(10), Dv(50), and Dv(90). %<10 μm.Data concerning droplet size distribution are summarized in Tables 21and 23.

The spray pattern is the shape of the plume when looking downward on thenasal spray unit as the product is emitted from the nasal spray unit.Spray pattern was also investigated as a function of device age andstorage. Ovality is the ratio of D_(max)/D_(min), where D_(max) andD_(min) are the length of the longest and shortest line respectively inmm that passes through the weighted center of mass drawn within theparameter of the spray pattern. A SPRAYVIEW, from PROVERIS measurementsystems, was used to measure spray pattern and plume geometry. Both theSprayview and Spraytec systems have been validated. Data concerningspray pattern are summarized in Tables 22 and 24. The procedures ofthese tests comply with the testing contained in the FDA's Guidance forIndustry (“Nasal Spray and Inhalation Solution, Suspension, and SprayDrug Products—Chemistry, Manufacturing, and Controls Documentation,”July 2002).

TABLE 21 Droplet size distribution from 2 mg naloxone intranasal device.Batch Storage Storage temp # orientation (° C.) Dv(90) (μm) % <10 μm 3cm spray 1 horizontal 25° 70.87 1.215 2 inverted 25° 70.05 1.218 2upright 25° 69.13 0.269 3 inverted 40° 66.74 1.628 3 upright 25° 67.21.112 3 upright 40° 67.2 1.112 6 cm spray 1 horizontal 25° 63.74 1.647 2inverted 25° 69.02 1.752 2 upright 25° 64.81 1.634 3 inverted 40° 66.521.713 3 upright 25° 69.36 0.777 3 upright 40° 69.36 0.777

TABLE 22 Spray pattern from 2 mg naloxone intranasal device. StorageStorage temp Batch # orientation (° C.) Ovality ratio 3 cm spray 2inverted 25° 1.165 3 inverted 40° 1.257 3 upright 40° 1.308 3 upright40° 1.278 3 upright 40° 1.308 4 inverted 25° 1.054 4 upright 25° 1.168 4upright 25° 1.204 6 cm spray 2 inverted 25° 1.684 3 inverted 40° 1.365 3inverted 40° 1.041 3 upright 40° 1.33 3 upright 40° 1.187 4 inverted 25°1.304 4 upright 25° 1.367 4 upright 25° 1.59

TABLE 23 Droplet size distribution from 4 mg naloxone intranasal device.Batch Storage Storage temp # orientation (° C.) Dv(90) (μm) % <10 μm 3cm spray 1 horizontal 25° 70.87 1.215 2 inverted 25° 73.85 0.524 3upright 40° 76.74 1.082 3 inverted 40° 73.86 1.467 6 cm spray 1horizontal 25° 66.74 1.647 2 inverted 25° 67.49 1.606 3 upright 40°80.99 1.031 3 inverted 40° 69.94 1.699

TABLE 24 Spray pattern from 4 mg naloxone intranasal device. StorageStorage temp Batch # orientation (° C.) Ovality ratio 3 cm spray 1upright 25° 1.511 2 upright 40° 1.557 3 inverted 25° 1.169 3 upright 40°1.215 3 inverted 40° 1.475 6 cm spray 1 upright 25° 1.435 2 upright 40°1.428 3 inverted 25° 1.077 3 upright 40° 1.164 3 inverted 40° 2.076

Pharmaceutical compositions comprising naloxone hydrochloride (1% w/v)were tested for stability in room temperature/light conditions, roomtemperature/dark conditions and in 25° C./60% RH (protected from light).It was tested for pH, purity, and impurities at an initial time point, 2months and 10 months. Results are given in Table 25.

TABLE 25 Naloxone storage stability. Assay Test (% of Storage intervallabel Impurities condition (months) Appearance pH claim) (area %)Initial Clear, colorless 4.5 101  Not detected solution 25° C./  2 Notanalyzed 4.5 Not Not analyzed 60% RH analyzed 10 Clear, colorless 4.5 950.2 solution Room 10 Clear, yellow 4.4 92 1.3 temperature/ solutionlight Room 10 Clear, colorless 4.5 97 0.3 temperature/ solution dark

Example 4 Reliability of Use by Untrained Personnel

The intranasal delivery provides a quick, simple and effective solutionfor those bystanders, friends or family members that are in a positionto give aid to an overdose victim.

Qualitative Study which consisted of 3 consecutive and iterative HumanFactors/Label Comprehension Pre-Tests, was conducted over a 5-day periodto assess the ability of subjects to understand the labelling (PatientInsert and Quick Start Guide (QSG)) and to demonstrate simulated use ofa naloxone nasal prototype device.

The purpose of this testing schedule was to learn and adjust thelabelling and materials in an iterative and accelerated manner. Theobjectives of the study were:

To evaluate the subject's ability to correctly demonstrate the steps forevaluating a patient for the medication, administering the medication,monitoring the patient and, if appropriate, giving a second dose, asinstructed in the QSG (Human Factors);

To evaluate the subject's ability to comprehend key messages in thePatient Insert (Comprehension);

To assess the study flow and study tools (Self-AdministeredQuestionnaire and Observer Checklist),

To evaluate 2 different labelling versions for clarity.

Post the qualitative studies the device and label were validated inquantitative studies

Two human factors validation studies were conducted in a generalpopulation (GP) of individuals 12 years of age and older. Formativeresearch was completed in advance of the validation work in order tooptimize the labeling and help inform the study design. The validationstudies were conducted in order to evaluate the ability of subjects tocorrectly complete 2 critical tasks (insert nozzle into nostril andpress plunger to release dose into nose) from the Quick Start Guide(QSG).

-   -   Study 1: The first study evaluated two devices, with two units        contained in the kit to be administered 2-3 minutes apart.    -   Study 2: The second study evaluated a single device.

Additionally, comprehension of key elements of the Patient Information(PI) section of the Prescribing Information was also evaluated. Thedesign for the Study 1 informed the design of the Study 2; the primaryendpoints and protocols for the studies were very similar. The methodsand findings of these two studies are summarized in Table 26 below.

TABLE 26 Reliability of intranasal naloxone administration by untrainedpersonnel. COMPARATIVE STUDY CRITERIA Study1 Study 2 Methodology StudyPopulation - General Population, 12 years of age and older ✓ ✓ Studypopulation included subgroups of low literate subjects (~25%) and ✓ ✓adolescent subjects ages 12-17 (~25%). None of the subjects wereprovided with any training on how to use the ✓ ✓ device. Included ‘StudyArms’: Both Arm 2 only   Arm 1 (Review QSG in Advance): Subjects werepresented with the Arm 1 (n = 53)   Quick Start Guide to review prior tothe demonstration (n = 32) &   Arm 2 (Do not review QSG in Advance):Subjects were presented Arm 2   with a ‘worst case’ scenario in whichthey had to use and interpret (n = 31)   the labeling at the time of anemergent situation, such as finding an   individual unconscious. PrimaryObjectives (Human Factors) - correct ✓ ✓ completion of the criticaltasks:   Insert nozzle into nostril (Task 2a)   Press plunger to releasedose into nose (Location -   Task 2b; Dose Released - Task 2c) SuccessThreshold (lower bound of the 95% exact confidence interval) 69% 73% forcombined critical tasks completion Secondary Objectives (Human Factors):✓a ✓   Check for response (Task 1a)   Call 911 (Task 3a)   Move toRecovery Position after administering dose (Task 3b) Primary Objectives(Comprehension): ✓ ✓   Product Indication (product use) (Q.1)   ProductIndication (medical treatment) (Q.2)   How NASAL should be used (Q.8)  Get emergency medical help after using NASAL (Q.6)   Signs of opioidoverdose (Q.7)   Potential withdrawal symptoms after use of NASAL (Q.4)Secondary Objectives (Comprehension): ✓ ✓   Whether NASAL can be usedfor overdoses not caused by     opioids (Q.3)   When a patient shouldtalk to a healthcare provider before use     (Q.5)   Who should not usethe product (Q.9) Inclusion Criteria: ✓ ✓ The following inclusioncriteria applied to all participants: 1. The subject was male or female,of any race. 2. The subject was 12 years of age or older 3. The subjectmust have been able to read, speak and understand English sufficientlyto understand the nature of the study procedures. 4. At the study site,the subject must have agreed to follow the specified instructions andprocedures and must have voluntarily signed the CDA and the InformedConsent/Assent form. If the subject was less than 18 years of age: aparent/guardian must have been present to sign the Consent/Assent formand give permission for adolescent to participate. Exclusion Criteria: ✓✓ The following exclusion criteria applied to all participants: 1. Thesubject had ever been trained or employed as a healthcare professional(physician, nurse, nurse practitioner, physician assistant, orpharmacist). 2. The subject or anyone in their household currentlyworked for a marketing, marketing consulting, or marketing researchcompany, an advertising agency or public relations firm, apharmaceutical company, a pharmacy, a managed care or health insurancecompany as a healthcare professional, a healthcare practice, or a publichealth agency such as Health and Human Services or the FDA. 3. Thesubject had, or could not remember if he/she had, participated in anyclinical trial, product label study or market research study in the pasttwelve (12) months. 4. The subject normally wore corrective lenses,contacts or glasses to read and did not have them with them. 5. Thesubject had any other impairment that would prevent him/her from beingable to read on his/her own. Results Primary Objectives (Human Factors):Yes - both Yes -   Success Threshold met? arms above above   (Correctperformance of both critical tasks) 69% LB 73% LB     Insert nozzle intonostril (Task 2a) threshold threshold     Press plunger to release doseinto nose    (Location - Task 2b; Dose Released - Task 2c) SecondaryObjectives (Human Factors): ✓b ✓   Two of three objectives tested acrossboth waves scored higher   than 70% PE:     Check for a Response (Task1a)     Immediately Call 911 (Task 3a)     Move to Recovery Position(Task 3b) scored lowest across both     waves, particularly for subjectswho did not review the QSG prior     to the demonstration PrimaryObjectives (Comprehension): ✓ ✓   4 objectives scored 90% PE or higheracross both waves:     Q.1 - Product Indication (product use)     Q.8 -How NASAL should be used     Q.6 - Necessary to get emergency medicalhelp after using     NASAL     Q.7 - Signs of opioid overdose   2objectives scored 77% PE or higher across both waves:     Q.4 -Potential withdrawal symptoms after use of NASAL     Q.2 - ProductIndication (medical treatment) Exploratory Objectives - (Comprehension):Scores Scores   Scores were relatively consistent across study waves:ranged ranged     Q.3 - Whether NASAL can be used for overdoses notcaused from from     by opioids 79%-92% 70%-93%     Q.5 - When a patientshould talk to a healthcare     provider before use     Q.9 - Who shouldnot use the product a Also included 2 additional secondary human factorsobjectives [Wait 2-3 minutes and assess effectiveness of 1st dose;Re-administer using a new unit (if needed)]; these were not applicablefor Study 2. b Study 1 included two additional secondary human factorsobjectives - Wait 2-3 minutes and assess effectiveness of 1st dose (Task4a); Re-administer using a new unit (if needed) (Task 4c). Subjects whoreviewed the QSG prior to the demonstration scored directionally higherthan subjects who did not for the actions related to these objectives.

CONCLUSION

Subjects demonstrated the ability to correctly perform both criticaltasks and performed better than the success threshold in both studies(Study 1—Arm 1: 90.6% PE, 74.98% LB; Study 1—Arm 2: 90.3% PE, 74.25% LB;Study 2: 90.6% PE, 79.34% LB), to use the device and deliver a dose ofthe medication safely and effectively without any training and with noprior review of instructions. Subjects did not demonstrate two secondarytasks as ably; only 59.4% of Arm 1 and 54.8% of Arm 2 correctlyadministered the dose within 2-3 minutes of the first dose, and 80.0%(Arm 1) and 70.0% (Arm 2) correctly administered a second dose.Comprehension scores were also very high for the most criticalcomprehension objectives [product indication (medical treatment),product indication (product use), get emergency medical help after usingproduct, how product should be used, sign of opioid overdose]. Theresults suggest that this product can be safely used by a bystanderpopulation with little or no training or advanced review ofinstructions.

OTHER EMBODIMENTS

The detailed description set-forth above is provided to aid thoseskilled in the art in practicing the present disclosure. However, thedisclosure described and claimed herein is not to be limited in scope bythe specific embodiments herein disclosed because these embodiments areintended as illustration of several aspects of the disclosure. Anyequivalent embodiments are intended to be within the scope of thisdisclosure. Indeed, various modifications of the disclosure in additionto those shown and described herein will become apparent to thoseskilled in the art from the foregoing description, which do not departfrom the spirit or scope of the present inventive discovery. Suchmodifications are also intended to fall within the scope of the appendedclaims.

This application incorporates by reference the disclosures of patentapplications Ser. No. 61/953,379, filed Mar. 14, 2014; U.S. 14/659,472,filed Mar. 16, 2015; PCT/IB2015/000941, filed Mar. 16, 2015; U.S.62/022,268, filed Jul. 9, 2014; U.S. 14/795,403, filed Jul. 9, 2015; andPCT/US15/39720, filed Jul. 9, 2015.

What is claimed is:
 1. A method of treating opioid overdose, the methodcomprising: delivering a 25-200 μL spray of a pharmaceutical solutionfrom a pre-primed device into a nostril of a patient, wherein the deviceis adapted for nasal delivery, and wherein the pharmaceutical solutioncomprises about 4 mg naloxone hydrochloride or a hydrate thereof,between about 0.005% and about 0.015% (w/v) of benzalkonium chloride,and an isotonicity agent.
 2. The method of claim 1, wherein thepharmaceutical solution comprises between about 0.2% and about 1.2%(w/v) of the isotonicity agent.
 3. The method of claim 2, wherein thepharmaceutical solution further comprises between about 0.1% and about0.5% (w/v) of a stabilizing agent and an amount of an acid sufficient toachieve a pH between about 3.5 and about 5.5.
 4. The method of claim 3,wherein: the isotonicity agent is sodium chloride; the stabilizing agentis disodium edetate; and the acid is hydrochloric acid.
 5. The method ofclaim 4, wherein the pharmaceutical solution comprises: about 4% (w/v)naloxone hydrochloride; about 0.74% (w/v) sodium chloride; about 0.01%(w/v) benzalkonium chloride; and about 0.2% (w/v) disodium edetate. 6.The method of claim 5, wherein the device has a single reservoircontaining approximately 125 μL of the pharmaceutical solution.
 7. Themethod of claim 6, wherein approximately 100 μL of the pharmaceuticalsolution is delivered by one actuation of the device.
 8. The method ofclaim 7, wherein the device comprises a reservoir, a piston, and a swirlchamber.
 9. The method of claim 6, further comprising storing the devicefor about twelve months or less at 25° C. and 60% relative humidityprior to actuating the device, wherein the device retains at least about100% of initial naloxone hydrochloride content at actuation.
 10. Themethod of claim 1, wherein the patient experiences a geometric meannaloxone C_(max) not less than about 3 ng/mL following a single spray.11. The method of claim 10, wherein the patient experiences a plasmanaloxone concentration such that the geometric mean of area under aplasma concentration versus time curve (AUC_(0-∞)) is not less thanabout 8 hr*ng/mL when time is extrapolated to infinity.
 12. A mistdelivered from a pre-primed device, wherein the mist comprises droplets,wherein the droplets comprise, in aggregate, about 4 mg of naloxonehydrochloride or a hydrate thereof, between about 0.005% and about 1%(w/v) of benzalkonium chloride, and an isotonicity agent, wherein nomore than about 10% of the droplets have a diameter less than 10 μm. 13.The mist of claim 12, wherein the mist comprises the isotonicity agentin a concentration between about 0.2% and about 1.2% (w/v).
 14. The mistof claim 13, wherein the isotonicity agent is sodium chloride.
 15. Themist of claim 12, wherein the mist takes the shape of a round plume withan ovality ratio less than 2.0.
 16. The mist of claim 12, wherein thenaloxone is at least 40% bioavailable.
 17. The mist of claim 16, whereinthe median droplet size is between about 30 μm and about 100 μm.
 18. Themist of claim 17, wherein approximately 50% of droplets have a diameterbetween about 30 μm and about 70 μm.
 19. The mist of claim 18, whereinapproximately 90% of droplets have a diameter less than about 100 μm.20. The mist of claim 19, wherein no more than approximately 2% ofdroplets have a diameter less than about 10 μm.
 21. The mist of claim12, wherein the mist stands adjacent to an aperture in a single-dosespray device or a bi-dose spray device.
 22. A method of treatingnarcotic-induced respiratory depression, the method comprising:delivering a 25-200 μL spray of a pharmaceutical solution from apre-primed device into a nostril of a patient in need thereof in amanner that delivers the pharmaceutical solution in a round spray plumewith an ovality ratio less than about 2.0 when measured at 3 cm, whereinthe device is adapted for nasal delivery, and wherein the spraycomprises about 4 mg naloxone hydrochloride or a hydrate thereof,between about 0.005% and about 0.015% (w/y) ref benzaikonium chloride,and an isotonicity agent wherein the patient experiences a geometricmean naloxone C_(max) not less than about 3 ng/ml, following a singlespray.
 23. The method of claim 22, wherein the pharmaceutical solutioncomprises between about 0.2% and about 1.2% (w/v) of the isotonicityagent.
 24. The method of claim 23, wherein the pharmaceutical solutionfurther comprises between about 0.1% and about 0.5% (w/v) of astabilizing agent.
 25. The method of claim 24, wherein thepharmaceutical solution further comprises an amount of an acidsufficient to achieve a pH between about 3.5 and about 5.5.
 26. Themethod of claim 25, wherein: the isotonicity agent is sodium chloride;the stabilizing agent is disodium edetate; and the acid is hydrochloricacid.
 27. The method of claim 26, wherein the acid is hydrochloric acidand wherein the pharmaceutical solution comprises: about 4% (w/v)naloxone hydrochloride; about 0.74% (w/v) sodium chloride as theisotonicity agent; about 0.01% (w/v) benzalkonium chloride; and about0.2% (w/v) disodium edetate as the stabilizing agent.
 28. The method ofclaim 22, wherein the plasma concentration versus time curve of naloxonein the patient has a t_(max) of less than 30 minutes.
 29. The method ofclaim 22, wherein the ovality ratio is less than about 1.5when measuredat 3 cm.
 30. The method of claim 22, wherein the device comprises aplunger that houses a container closure comprising a vial comprising anopening, a cannula, and a rubber stopper, wherein the stopper isconfigured to occlude the opening of the vial, and wherein the cannulais configured such that the cannula can pierce the stopper when theplunger applies sufficient force to the cannula.